Stroke Essentials and Points

Stroke Essentials

Second Edition

Adrian J. Goldszmidt, MD Chief, Department of Neurology, Sinai Hospital

Sandra and Malcolm Berman Brain & Spine Institute at LifeBridge Health

Instructor of Neurology Johns Hopkins School of Medicine

Baltimore, Maryland

Louis R. Caplan, MD Director of Cerebrovascular Disease

Beth Israel Deaconess Medical Center Professor of Neurology Harvard Medical School Boston, Massachusetts

2010

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ABOUT THE AUTHORS

Adrian J. Goldszmidt, MD, is chief of the Department of Neurology at The Sandra and Malcolm Berman Brain & Spine Institute at LifeBridge Health and director of the Stroke Center at Sinai Hospital of Baltimore, as well as an instructor in neurology at The Johns Hopkins University School of Medicine. After completing medical school at Harvard, he trained in neurology at Harvard’s Longwood program in Boston, then completed a stroke fellowship at New England Medical Center. Dr. Goldszmidt has been an investigator in numerous acute stroke trials and has research interests in platelet function in stroke. He is actively involved in patient care.

Louis R. Caplan, MD, is director of cerebrovascular disease at Beth Israel Deaconess Medical Center, Boston, Massachusetts; professor of neurology, Harvard Medical School, Boston, Massachusetts; and one of the world’s leading authorities on stroke. Dr. Caplan graduated cum laude from Williams College and summa cum laude from the University of Maryland Medical School, as well as valedictorian of his graduating class. During his distinguished career, he served as chair of the neurol-ogy department at Beth Israel Hospital in Boston, Neurologist-in-chief at Michael Reese Hospital in Chicago and the New England Medical Center in

Boston, professor of neurology at the University of Chicago, and professor and chairman of the department of neurology and professor of medicine at Tufts Medical Center in Boston. Dr. Caplan also served as chairman of the Stroke Council of the American Heart Association and as chair of numerous neurologic and stroke organizations. At Beth Israel Hospital, he founded the Harvard Stroke Registry. Dr. Caplan is the author or editor of 35 books, and he has contributed more than 600 scholarly articles to the medical literature. He also serves or has served on the editorial boards of 29 medical journals. He speaks nationally and interna-tionally on stroke and has delivered 36 named lectures in neurology and medicine. Dr. Caplan has received several teaching awards, as well as the Distinguished Achievement Award from the American Heart Association. He lives in Brookline, Massachusetts.

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DEDICATION

For stroke patients

now and in the future

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TABLE OF CONTENTS

SECTION 1: DIAGNOSIS, EVALUATION, AND TREATMENT OF STROKE ............................ 1

1. Overview of Stroke ................................. 3 Classifi cation ............................................. 4 Detection and Evaluation of Stroke ........... 5

History, Physical Exam, and Laboratory Testing ............................... 5

Imaging ................................................. 8 CT/MRI ............................................... 8 Doppler Ultrasound ............................ 8 Magnetic Resonance and Computed

Tomography Angiography ............... 8 Cerebral Angiography ......................... 8 Lumbar Puncture ................................ 8 Echocardiogram .................................. 8 Electrocardiography ............................ 9 Holter Monitoring ............................... 9 Electroencephalography ...................... 9

2. Ischemic Stroke ..................................... 11 Clinical Features ...................................... 13 Overview of Treatment ............................ 15 Presentation ............................................ 16 Lytic-Eligible Patients ................................ 18 Lytic-Ineligible Patients ............................. 18

Antiplatelet Therapy ............................. 18 Heparin Therapy ................................... 19

Clinical Trials ..................................... 19 Recommendations ............................ 19 Heparin Dose .................................... 19

Measures to Prevent Recurrent Stroke ..... 19 Large Artery Atherothrombosis ...............20

Internal Carotid Artery ...................... 20 Vertebral Artery ................................ 20 Intracranial Disease ........................... 21

Brain Embolism ........................................ 22 Atrial Fibrillation ................................ 22 Acute Myocardial Infarction .............. 22 Valvular Heart Disease ....................... 22 Cardiomyopathy ............................... 23 Atrial Myxoma .................................. 23 Paradoxical Embolism ....................... 23 Other Cardiac Conditions .................. 24

Lacunar Stroke ........................................ 24 Transient Ischemic Attack ........................ 25

3. Thrombolytic Therapy for Acute Ischemic Stroke ..................................... 27 Overview ................................................. 28

Baseline Evaluation ............................... 30

Dosing and Administration ................... 30 Post-Lytic Care ...................................... 30

General Measures ............................. 30 Inclusion and Exclusion Criteria ............. 31 Management of Elevated

Blood Pressure .................................. 32 Management of Lytic Complications .... 32 NIH Stroke Scale .................................. 33

4. Brain Hemorrhage ................................ 35 Clinical Features ...................................... 36 Subarachnoid Hemorrhage ...................... 38

Ruptured Saccular (Berry) Aneurysm .... 38 Overview .......................................... 38 Treatment ......................................... 39

Ruptured AV Malformation .................. 39 Overview .......................................... 39 Treatment ......................................... 39

Complications ...................................... 40 Rebleeding ........................................ 40 Vasospasm ....................................... 40 Increased Intracranial Pressure .......... 40 Hydrocephalus .................................. 40 Intracerebral Hematoma ................... 40 Cardiac ............................................. 40 Hyponatremia ................................... 40

Intracerebral Hemorrhage ....................... 41 Hypertension ........................................ 41 Other Causes ....................................... 42 Cerebellar Hemorrhage ........................ 42 Subdural and Extradural Hematoma ..... 42

5. Stroke-Related Complications .............. 45 Treatment ............................................... 46

Increased Intracranial Pressure ............. 46 Seizures ................................................ 47 Deep Venous Thrombosis ..................... 47 Pulmonary Embolus .............................. 47 Depression ........................................... 47 Hypertension ........................................ 48 Myocardial Infarction ........................... 48 Arrhythmias ......................................... 48 Infections and Sepsis ............................ 49 Upper Gl Bleed ..................................... 49 Hyponatremia ...................................... 49 Respiratory Depression ......................... 49 Depressed Consciousness ..................... 49 Fever .................................................... 49 Malnutrition ......................................... 49 Contractures ........................................ 49 Decubitus Ulcers ................................... 49

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6. Miscellaneous Topics in Cerebrovascular Disease ...................... 51 Asymptomatic Carotid Artery Stenosis ..... 52

Stenosis >60% ..................................... 52 Stenosis <60% ..................................... 52

Unruptured Aneurysm ............................. 52 Carotid Endarterectomy ........................... 52 Extracranial-Intracranial Bypass ................ 53 Carotid and Vertebral Artery Stenting ..... 53

7. Stroke Pitfalls ........................................ 55

8. Controversies in Stroke Management .....63 Stroke and Patent Foramen Ovale ........... 64

Antiplatelet Agents or Anticoagulation with Warfarin ................................... 64 PFO Closure ...................................... 65

Large Hemispheric Stroke Within 3–6 Hours ............................................ 65 IV tPA .................................................. 65 IA tPA .................................................. 65 MERCI Retriever ................................... 65

Hemicraniectomy for Malignant MCA Stroke ......................................... 66

Craniotomy/Evacuation for Supratentorial ICH ............................... 67 Benefi ts of Surgery ............................... 68 Contraindications of Surgery ................ 68

Antiplatelet Agents for Secondary Stroke Prevention ................................. 68 Aspirin ................................................. 68 Clopidogrel or Aspirin and Extended-

Release Dipyridamole ....................... 69 Timing of Carotid Surgery After Recent

Stroke .................................................. 70 Early vs Late ......................................... 70

Acute Mild Stroke .................................... 70

SECTION 2: CEREBROVASCULAR & CARDIOVASCULAR RISK REDUCTION ..... 73

9. Overview ............................................... 75 Annual Risk Percentage ........................... 76 Modifi able Risk Factors ............................ 77

10. Therapeutic Lifestyle Changes ........... 79 Diet Modifi cation ................................... 80

Therapeutic Lifestyle Changes Diet ..... 81 Recommendations ............................. 81 Dietary Options for Risk Reduction ..... 83

Mediterranean-Style Diet ....................... 84 Mediterranean Diets .......................... 84 Other Studies ..................................... 85 Recommendations ............................. 85

Basic Components .......................... 86 How to Incorporate ........................ 87

Physical Activity ..................................... 89 Overview ............................................ 89 Amount and Type of Exercise ............. 89 Stress Testing ..................................... 90

Weight Control ...................................... 90 Overview ............................................ 90 Classifi cation of Obesity ..................... 90 Evaluation of Obesity ......................... 91 Treatment of Obesity ......................... 91

Antiobesity Drugs Approved by the FDA ...................................... 93

Smoking Cessation ................................ 94 Overview ............................................ 94 Guidelines .......................................... 95

Strategies to Assist Patients to Quit ...96 Drug Therapy ................................. 98

11. Antiplatelet and Antithrombotic Therapy for the Prevention of Recurrent Ischemic Stroke ................ 101 Antiplatelet Therapy ............................ 102

Atherothrombosis as a Systemic Disease 102 Role of the Platelet ........................... 102 Antiplatelet Monotherapy ................ 102

Aspirin .......................................... 102 Clopidogrel ................................... 104 Ticlopidine .................................... 105

Combination Antiplatelet Therapy .... 105 Aspirin Plus Dipyridamole .............. 106 Aspirin Plus Clopidogrel ................ 106

Summary ......................................... 108 Antithrombotic Therapy ....................... 109

12. Control of Hypertension ................... 113 Diagnosis and Evaluation ..................... 114

Proper Blood Pressure Measurement ............................... 116

Excluding Conditions Leading to Overdiagnosis ............................... 118 White-Coat Hypertension .............. 118 Pseudohypertension ..................... 118

Assessing Target Organ Damage ..... 118 Detecting Secondary Hypertension ... 118

Treatment of Hypertension .................. 119 Blood Pressure Goals ........................ 119 Drug Therapy ................................... 119

Initial Therapy ............................... 119 Intensifi cation of Therapy ............. 120 Combination Therapy ................... 121 Stepdown Therapy ....................... 121

Optimizing Patient Compliance ........ 121

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13. Control of Dyslipidemia .................... 123 Diagnosis, Evaluation,

and Treatment ................................. 124 Lipoprotein Analysis ......................... 124 Secondary Causes ............................ 125 Genetic Dyslipidemia ........................ 125 LDL/Non-HDL Cholesterol Goals ....... 125 Metabolic Syndrome ........................ 125

Treatment of Elevated LDL Cholesterol .... 126 Treatment of Low HDL Cholesterol ...... 126 Treatment of Elevated Triglyceride ....... 126 Drug Therapy for Dyslipidemia ............. 128

14. Other Measures to Prevent Atherothrombosis and Stroke ......... 133 Control of Diabetes Mellitus ................ 134 ACE Inhibitors ...................................... 134 Low-Dose Fish Oil ................................ 135 Arterial Revascularization ..................... 135

Carotid Endarterectomy ................... 135 Carotid Angioplasty and Stenting ..... 135

Folic Acid ............................................. 136 Antioxidants ........................................ 136 Hormone Replacement Therapy ........... 137 Citicoline ............................................. 137

SECTION 3: CLINICAL TRIALS .................. 139

15. Clinical Trials ...................................... 141 Stroke Prophylaxis in Atrial

Fibrillation (AF) .................................. 142 Antiplatelet Therapy for TIAs or

Minor Strokes .................................. 145 Antiplatelet/Antithrombotic Therapy

for Acute Stroke .............................. 149 Randomized Thrombolysis Trials .......... 152 Carotid Endarterectomy Trials .............. 156 Cerebral Angioplasty/Stent Trials ......... 157 Miscellaneous Stroke Trials .................. 159 Hypertension Trials .............................. 160 Dyslipidemia and Other

Risk Reduction Trials ......................... 163 Neuroprotection Trials ......................... 168 Intracerebral Hemorrhage Trials ........... 170

SECTION 4: FILM LIBRARY ...................... 173

16. Film Library ........................................ 175

References and Suggested Readings . .... 187

Index ........................................................ 193

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ACKNOWLEDGMENTS

We wish to acknowledge the people who made signifi cant contributions to this book: Christie Ballantyne, MD; Antonio Gotto, Jr, MD; Norman Kaplan, MD; James O’Keefe, MD; Mark Weber, MD; and Rebecca Smith. In addition, we wish to thank Michael Stein, Tzipora Sofare, and Wes Dixon for their technical support for this edition.

Adrian J. Goldszmidt, MD Louis R. Caplan, MD

NOTICE

Stroke Essentials has been developed as a concise, practical, and authoritative guide for the treatment of patients with cerebrovascular disease. The clinical recommendations set forth in this book are those of the authors and are offered as general guidelines, not specifi c instructions for individual patients. Clinical judgment should always guide the physician in the selection, dosing, and duration of drug therapy for individual patients. Not all medications have been accepted by the US Food and Drug Administration for indications cited in this book, and drug recommendations are not necessarily limited to indications in the package insert. The use of any drug should be preceded by careful review of the package insert, which provides indications and dosing approved by the US Food and Drug Administration. The infor-mation provided in this book is not exhaustive, and the reader is referred to other medical ref-erences and the manufacturers’ product literature for further information. Clinical use of the information provided and any consequences that may arise from its use are the responsibility of the prescribing physician. The authors, editors, and publisher do not warrant or guarantee the information herein contained and do not assume and expressly disclaim any liability for errors or omissions or any consequences that may occur from use of this information.

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CONTRIBUTORS

Christie M. Ballantyne, MD Clinical Director, Section of Atherosclerosis Professor of Medicine Baylor College of Medicine Director, Center for Cardiovascular Disease Prevention Methodist DeBakey Heart Center Houston, Texas Dyslipidemia and Risk Reduction

Antonio M. Gotto, Jr, MD, DPhil The Stephen and Suzanne Weiss Dean

Professor of Medicine Provost for Medical Affairs The Weill Medical College of Cornell University New York, New York Dyslipidemia and Risk Reduction

Norman M. Kaplan, MD Professor of Medicine University of Texas Southwestern

Medical Center Dallas, Texas Hypertension and Risk Reduction

James H. O’Keefe, Jr, MD Director, Preventive Cardiology Mid America Heart Institute Clinical Professor of Medicine University of Missouri School of Medicine Kansas City, Missouri Dyslipidemia and Risk Reduction

Mark A. Weber, MD Professor of Medicine Associate Dean SUNY Downstate College of Medicine Brooklyn, New York Hypertension and Risk Reduction

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ABBREVIATIONS

ABC airway, breathing, circulation ACA anterior cerebral artery ACC American College of Cardiology ACE angiotensin converting enzyme ADP adenosine diphosphate AF atrial fi brillation AHA American Heart Association ASA atrial septal aneurysm ASD atrial septal defect ATP Adult Treatment Panel (National

Cholesterol Education Program) AV arteriovenous AVM arteriovenous malformation bid twice daily BMI body mass index BP blood pressure CABG coronary artery bypass grafting CBC complete blood count CEA carotid endarterectomy CHD coronary heart disease CI confi dence interval CI contraindication CNS central nervous system COPD chronic obstructive pulmonary disease CSF cerebrospinal fl uid CT computed tomography CTA CT angiography DBP diastolic blood pressure DHA docosahexaenoic acid dL deciliter DVT deep venous thrombosis EBCT electron beam computed

tomography ECG electrocardiogram EEG electroencephalogram EPA eicosapentaenoic acid FDA Food and Drug Administration Gl gastrointestinal gm gram GP glycoprotein HEENT Head Ears Eyes Nose Throat HDL high-density lipoprotein IA intraarterial ICA internal carotid artery ICH intracerebral hemorrhage ICP intracranial pressure INR international normalized ratio IV intravenous/intravenously kg kilogram L liter LDL low-density lipoprotein LP lumbar puncture Lp(a) lipoprotein(a) LV left ventricular; left ventricle LVH left ventricular hypertrophy

MAO monoamine oxidase (inhibitor) max maximum MCA middle cerebral artery mcg microgram mcL microliter mg milligram MGH Massachusetts General Hospital MI myocardial infarction min minute/minutes mL milliliter mmHg millimeters of mercury mOsm milliosmole; one thousandth

of an osmole MRA magnetic resonance angiography MRI magnetic resonance imaging MRS modifi ed Rankin scale NCEP National Cholesterol Education

Program NHLBI National Heart, Lung, and

Blood Institute NIH National Institutes of Health NINDS National Institute of Neurologic

Diseases and Stroke NRT nicotine replacement therapy OTC over the counter PCA posterior cerebral artery pCO

2 partial pressure of carbon dioxide PET positron emission tomography PFO patent foramen ovale PO per os—by mouth; oral PT prothrombin time PTT partial thromboplastin time q__hr every __ hours q__d every __ days RCT randomized controlled trial RDA recommended daily allowance RRR relative risk reduction rt-PA recombinant tissue plasminogen

activator SAH subarachnoid hemorrhage SBP systolic blood pressure SiADH syndrome of inappropriate antidiuretic

hormone secretion SPECT single photon emission computed

tomography SQ subcutaneous/subcutaneously TCD transcranial Doppler TIA transient ischemic attack tid three times daily TLC therapeutic lifestyle changes tPA tissue plasminogen activator TXA

2 thromboxane A 2

VLDL very low-density lipoprotein WBC white blood cell (count) WHI Women’s Health Initiative

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SECTION 1

DIAGNOSIS, EVALUATION, AND TREATMENT OF STROKE

Chapter 1. Overview of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Chapter 2. Ischemic Stroke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Chapter 3. Thrombolytic Therapy for Acute Ischemic Stroke . . . . . . . . . . . . . . . . . . 27 Chapter 4. Brain Hemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Chapter 5. Stroke-Related Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Chapter 6. Miscellaneous Topics in Cerebrovascular Disease . . . . . . . . . . . . . . . . . . 51 Chapter 7. Stroke Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Chapter 8. Controversies in Stroke Management . . . . . . . . . . . . . . . . . . . . . . . . . . 63

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Chapter 1

Overview of Stroke


Figure 1.1. Classifi cation of Stroke

Stroke

Brain ischemia(80%)

Thrombosis(30%)

Largearteries(10%)

Penetratingarteries

(Lacunar)(20%)

Cardiogenic(20%)

Artery-to-artery

(15%)

Aorticdebris(10%)

Saccular“berry”

aneurysm(7%)

Non-aneurysmal

(3%)

Systemichypoperfusion

(5%)

Embolism(45%)

Subarachnoid(10%)

Subdural,extradural

(2%)

Brain hemorrhage(20%)

Intracerebral(8%)

Stroke is the third most common cause of death in developed countries, behind cardiovascular disease and cancer. Each year, nearly 700,000 Americans develop strokes, and stroke results in nearly 150,000 deaths. At any one time, 5.8 million people in the United States have had strokes, resulting in stroke-related healthcare costs of nearly $70 billion per year. In addition, 11% of Americans aged 55--64 have had silent cerebral infarctions; the prevalence increases to 40% at age 80 and 43% by age 85. Strokes are broadly classifi ed into ischemic and hemorrhagic strokes (Figure 1.1, Table 1.1). Ischemic strokes account for 80–85% of strokes and are subdivided into large artery atherothromboses, brain embolism, lacunar stroke, and systemic hypoperfusion (Chapter 2). Brain hemorrhages account for the remaining 15–20% of strokes and are subdivided into intracerebral hemorrhage, subarachnoid hemorrhage, and subdural/extradural hematoma (Chapter 4). The distinction between ischemic stroke and hemorrhagic stroke is crucial: early, appropriate use of thrombolytic therapy reduces the risk of moderate or severe disability by 30% in ischemic stroke but is contraindicated in hemorrhagic stroke. For every 100 patients treated with IV tissue plasminogen activator (tPA), approximately 11 additional patients will have a favorable outcome over the following year (Chapter 3). Aggressive management of stroke-related complications (Chapter 5) and consistent application of cerebrovascular and cardiovascular risk reduction measures (Chapters 9–14) are also important for prognosis.

Stroke Essentials provides a concise, authoritative, and practical guide to the detection, evaluation, and treatment of stroke. Primary and secondary prevention measures are also emphasized, forming the basis for a management strategy aimed at halting the progression of atherosclerosis, stabilizing rupture-prone plaques, preventing arterial thromboembolism, and improving prognosis. The initial evaluation and management of stroke are summarized in Figure 1.2.

4 S t r o k e E s s e n t i a l s


Table 1.1. Ischemic vs. Hemorrhagic Stroke: General Features

Ischemic Stroke Hemorrhagic Stroke

Incidence 80–85% of strokes 15–20% of strokes

Patho-physiology

Large artery atherothrombosis; brain embolism; intracranial atherosclerosis; lipohyalinosis of small, penetrating vessels.

Rupture of berry aneurysm, AVM; severe hypertension; bleeding diathesis; trauma.

Presentation Neurologic defi cit usually in distribution of one vascular territory. TIA in 30–50%; headache, decreased consciousness uncommon.

Neurologic defi cit not necessarily limited to one vascular territory. TIA uncommon. Headache, vomiting, decreased consciousness common.

Initial treatment

Large artery atherothrombosis:tPA within 4.5 hours; otherwise, aspirin. Cardiogenic embolism: IV tPA within 4.5 hr; IA tPA within 6 hr; MERCI device within 8 hr; otherwise, heparin or aspirin Lacunar stroke: empiric antiplatelet therapy, control of blood pressure.

SAH: clipping, coiling, coating, or trapping of berry aneurysm (early); excision or embolization of AVM (late); nimodipine to prevent vasospasm. ICH: control of hypertension, bleeding diatheses; surgical drainage of large hematomas. Subdural/extradural hematoma: surgical drainage if large.

DETECTION AND EVALUATION OF STROKE

A. History, Physical Examination, Laboratory Testing. Acute ischemic stroke presents with sudden onset of a focal neurologic defi cit of presumed vascular origin. The diagnosis requires exclusion of brain hemorrhage and nonvascular mimics: seizure with postictal neurologic defi cit, subdural hematoma, brain tumor, brain abscess, encephalitis, complicated migraine, or glucose abnormalities. The primary purpose of the initial evaluation is to identify the type of stroke (ischemic or hemorrhagic) and to determine whether the patient is eligible for thrombolytic or other therapy. IV thrombolytic therapy has been shown to be effective if given within the fi rst 4.5 hours in the absence of cerebral hemorrhage or other exclusion criteria (Table 1.1). While not FDA approved beyond 3 hours after symptom onset, the ECASS III trial (see Chapters 3 and 15) (N Engl J Med 2008;259:1318–1329) found benefi t to IV recombinant tissue plasminogen activator (rt-PA) in patients up to 4.5 hours after symptom onset. Following the publication of ECASS III, an American Stroke Association Science Advisory (Stroke 2009;40:2945–2958) advocated for the expansion of the time window for acute ischemic stroke treatment to 4.5 hours, with additional exclusion criteria for patients beyond 3 hours. rt-PA is also occasionally used beyond 4.5 hours in selected circumstances. Intraarterial (IA) thrombolysis is used at many centers for patients with disabling strokes less than 6 hours old in the

Chapter 1. Overview of Stroke 5


Figure 1.2. Initial Evaluation and Management of Stroke

Stroke

Alert and stable Impaired consciousness

• Assess ABCs and vital signs• Secure airway• Attach ECG monitor, pulse oximeter, BP cuff• Start IV (normal saline 30 mL/hr)• Determine arterial blood gas level

• CT or MRI• Blood tests: Platelets, CBC, PT/PTT, electrolytes, glucose

Contact neurologist, neurosurgeon, or both.Further stabilization prior to urgent CT scanwithout contrast:• Treat DBP �120 mmHg• Control seizures: fosphenytoin (20 mg/kg at rate not to exceed 150 mg/min) or at the direction of neurologist• Treat arrhythmias

ICH or SAH:• Request neurosurgical evaluation for possible surgery• Reverse any anticoagulants• Nimodipine for SAH

Does the CT or MRI show hemorrhage?

No YesDo you still suspect SAH withnegative CT?

Perform LP

Blood foundon LP?

• Begin oxygen by nasal cannula• Review history, symptoms• Perform physical/neurologic exam 12-lead ECG, portable chest x-ray, electrolytes, glucose, CBC, platelets, fibrinogen, PT/PTT

No

No Yes

Acuteischemicstroke

(Figure 2.3,p. 17)

Yes

•

anterior circulation. When the occlusion involves the basilar artery, IA thrombolysis may be successful even after more than 12 hours of ischemia. The MERCI (Mechanical Embolus Removal in Cerebral Ischemia) device is FDA approved to remove clot from the proximal cerebral vasculature within eight hours of symptom onset. The initial history and physical examination are also used to assess the extent of neurologic dysfunction and to identify risk factors for atherothrombosis and comorbid medical conditions (Table 1.2).Laboratory testing is used to identify a potential cause of stroke (e.g., hyperviscosity syndrome, coagulopathy), to detect stroke-related complications (e.g., hyponatremia due



to SiADH), to establish baseline coagulation parameters, and to identify risk factors for generalized atherosclerosis (e.g., dyslipidemia). Vascular imaging (MRA, CTA, ultrasound) is used to detect the presence and location of occlusive thromboemboli.

Table 1.2. Clinical Evaluation of the Stroke Patient

History

• TIME: It is important that an accurate time of symptom onset be established; if the patient is unable to give a history, attempt to establish the time the patient was last seen well.

• Activity at time of stroke.• Temporal progression of symptoms (e.g., maximal at onset, gradual worsening, worsening

in step-like fashion).• Past history of stroke or TIA.• Accompanying signs: headache, neck pain, vomiting, decreased consciousness.• Risk factors/history of vascular disease: hypertension, dyslipidemia, MI, angina, palpitations,

rheumatic heart disease, heart failure, aortic aneurysm, peripheral arterial disease, smoking, diabetes mellitus.

• Nonatherosclerotic conditions associated with focal neurologic defi cit: history of seizures, migraine, brain tumor, cerebral aneurysm, head trauma, multiple sclerosis, blood dyscrasia, illicit drug use.

Physical Examination

• Vital signs; neurologic exam.• HEENT exam for head trauma, retinal changes (hypertensive, cholesterol crystals,

papilledema, subhyaloid hemorrhage).• Neck exam for bruits.• Heart exam for murmurs, gallops, ventricular dysfunction, pulmonary hypertension.• Abdominal exam for bruits, aneurysm.• Peripheral vascular exam for bruits, decreased pulses, ischemic skin changes, petechiae,

or evidence of distal embolization.

Laboratory Testing

• Complete blood count to identify potential cause of stroke: hematocrit >60%; WBC >150,000/mm3; platelets >1 million/mm3 or <20,000/mm3; evidence of sickle cell anemia or other hemoglobinopathies.

• Sedimentation rate (elevated in tumor, infection, vasculitis).• Serum glucose (hyperglycemia may worsen acute outcome; hypoglycemia may cause focal

neurologic changes).• Electrolytes.• Lipid profi le and fi brinogen.• PT, PTT, and INR to detect coagulopathies and for use as a baseline prior to anticoagulation

therapy.• Anticardiolipin antibodies.• Rapid plasma reagin for neurosyphilis.• Urine screen for cocaine or amphetamines, if suspected.



B. Imaging. All patients with suspected stroke should have an emergency unenhanced CT scan or MRI to differentiate ischemic from hemorrhagic stroke and to identify tumor or mass effect (suggesting large stroke). Ischemic stroke is the most likely diagnosis when the CT scan does not show hemorrhage, tumor, or focal infection, and the history does not suggest migraine, hypoglycemia, encephalitis, or SAH.

1. CT/MRI CT/MRI is used to determine the location, type (ischemia or hemorrhage), and complications of stroke (edema, mass effect, hydrocephalus). It is also used to exclude nonvascular causes of neurologic symptoms (tumors, hydrocephalus). MRI is more sensitive than CT scan for detecting brain infarction within the fi rst 72 hours and for evaluating the posterior fossa (brainstem and cerebellum), but CT can more easily differentiate hemorrhage from ischemia in acute lesions. Diffusion/perfusion-weighted MRI is particularly useful in identifying infarcted brain and underperfused brain regions at risk for infarction if reperfusion does not occur. Using contrast dye, CT perfusion studies can be done quickly in an emergency setting. The sensitivity of CT scan for detecting subarachnoid blood drops from 95% on day 1 to 50% at 1 week. LP is required for suspected SAH in patients with normal CT.

2. Doppler ultrasound. Duplex ultrasound is warranted to assess stenosis or occlusion of the carotid and vertebral arteries in the neck. TCD can be used to assess the direction and velocity of blood fl ow in the circle of Willis and to identify stenotic or occlusive vascular lesions in the anterior and posterior circulations. TCD can also be used to detect silent emboli and right-to-left vascular shunts.

3. MRA and CTA. MRA is used to screen for severe occlusive disease of extracranial arteries and intracranial large arteries. It is also used to screen for aneurysms in patients with predisposition (e.g., fi bromuscular dysplasia, polycystic kidneys). CTA is less prone to artifact from turbulence or complex fl ow patterns than is MRA.

4. Cerebral angiography. Angiography is used to defi ne the nature, location, and severity of vascular occlusive disease and to identify vascular abnormalities leading to brain hemorrhage (saccular aneurysm, AVM). Cerebral angiography is best used in conjunction with brain imaging (CT, MRI) and noninvasive vascular screening modalities (ultrasound, MRA, CTA).

5. Lumbar puncture. LP is used to diagnose SAH when CT/MRI are unavailable or negative (i.e., when bleeding is minor or several days old); the absence of blood on LP excludes the diagnosis of SAH. LP is also important when CNS infection (meningitis, meningovascular syphilis) is suspected.

6. Echocardiogram. Echocardiography is used to assess the nature and extent of myocardial/valvular disease when cardiogenic embolism is suspected to be the etiology of stroke. Transesophageal echo is more sensitive than transthoracic echo for the detection of aortic atherothrombotic debris, aortic dissection, atrial septal aneurysms, left atrial clot, infectious endocarditis, and shunts.



7. Electrocardiography. The ECG is used to detect myocardial ischemia/infarction, arrhythmias, and chamber enlargement that suggests cardiomyopathy or valvular heart disease.

8. Holter monitoring. Ambulatory ECG monitoring is used to detect paroxysmal arrhythmia when suspected as a cause of cardiogenic embolism.

9. Electroencephalography. EEG is useful for suspected seizures but not for clarifi cation of stroke subtype or stroke severity.



Chapter 2

Ischemic Stroke

77890_CH02_Print.indd 1177890_CH02_Print.indd 11 10/23/09 1:16:29 PM10/23/09 1:16:29 PM

Figure 2.1. Common Sites and Mechanisms of Ischemic Stroke

Adapted from: Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001;119:300S–330S.

Atrial fibrillation

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emboli

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More than 80 percent of strokes are ischemic in origin and are caused by thrombotic or thromboembolic arterial occlusion. The most common sites of clot origin include the extracranial cerebral arteries, the heart (atrial fi brillation, mitral valve disease, LV thrombus), the small penetrating arteries of the brain (lacunar stroke), and aortic arch plaque (Figure 2.1). Ischemic stroke is subdivided into large artery atherothrombosis, brain embolism, lacunar stroke, and systemic hypoperfusion (Table 2.1). Ischemic stroke typically presents as a focal neurologic defi cit in the distribution of a single blood vessel (Figure 2.2). Symptoms may be maximal at onset, wax and wane, progressively worsen, or deteriorate in stepwise fashion. Vomiting and loss ofconsciousness are rare.



Table 2.1. Ischemic Stroke: Clinical Features

Large-Artery Thrombosis Brain Embolism Lacunar Infarct Hypoperfusion

Risk factors Smoking, coronary artery disease, dyslipidemia, diabetes, males, peripheral arterial disease, obesity.

Atrial fi brillation, valvular disease, LV thrombus, cardiomyopathy, coronary artery disease, aortic arch plaque.

Hypertension, diabetes, polycythemia.

All forms of shock.

Onset of neurologic defi cit

Preceded by TIAs in 50%. Often occurs during sleep (i.e., patient awakes with neurologic defi cit). Neurologic changes often fl uctuate in a stepwise progressive or remitting fashion, due to recanalization, rethrombosis, and changes in collateral blood fl ow.

Sudden in 80%, with maximal defi cit at onset. Others show stepwise progression during the fi rst 24 hr. MCA syndrome is the most common presentation: Contralateral sensorimotor defi cit (arm/face > leg), aphasia (dominant hemisphere), unawareness of defi cit (non-dominant hemisphere) ± quadrantanopsia.

Fluctuating, progressive stepwise, or remitting. May gradually worsen over hours to days. Preceded by TIAs in 25%. Several distinct lacunar syndromes (pp. 24–25).

Begins with systemic disorder.

Associated symptoms

Headache before, at, or after onset. Vomiting, loss of consciousness are rare.

Neurologic defi cit is usually maximal at onset. Headache at or after onset. Vomiting, decreased consciousness are uncommon.

Usually none (i.e., alert without headache or vomiting).

Pallor, sweating, hypotension.

Chapter 2. Ischemic Stroke 13



Stroke location Superfi cial cortex (most often MCA), cerebellum, or territory of PCA.

Same as for large artery thrombosis.

Deep brain structures (basal ganglia, cerebral white matter, thalamus, pons, cerebellum).

Border zone between anterior, middle, and posterior cerebral arteries, or between posteroinferior, anteroinferior, and superior cerebellar arteries.

Imaging CT: low-density lesion (dark). May take hours to days before scan becomes positive. MRI: Diffusion bright; ADC dark within minutes. T1-weighted images: dark; T2-weighted images bright within hours.

Same radiographic appearance as infarcts in large artery thrombosis. Lesions tend to be wedge shaped; superfi cial only or superfi cial and deep.

Same radiographic appearance as infarcts in large artery thrombosis. Lesions are small (~1 cm), involve the deep cerebral white matter, basal ganglia, pons, or cerebellum.

Same radiographic appearance as infarcts in large artery thrombosis. Lesions usually bilateral in the watersheds, as described above.

Treatment Thrombolytic therapy for onset <4.5 hr. Aspirin ± heparin for others. CEA (or stenting) for moderate or severe stenosis.

Thrombolytic therapy for onset <4.5 hr. Heparin, warfarin, aspirin, antiarrhythmic, aneurysmectomy, repair of ASD, or resection of atrial myxoma, depending on source of embolism.

Thrombolytic therapy for onset <4.5 hr, although the effectiveness in this setting has not been shown. Long-term control of hypertension ± antiplatelet therapy. Maintenance of blood pressure acutely.

Maintenance of blood pressure with fl uids, vasopressors, intra-aortic balloon pump until specifi c therapy can be instituted.

Table 2.1. Ischemic Stroke: Clinical Features (cont'd)




Prognosis Mortality 20% at 1 month and 25% at 1 year. Two-thirds of survivors lead an independent existence. Thrombolytic therapy reduces signifi cant disability by 30%. Early cause of death is herniation (<72 hr) and cardiac disease or sepsis (>72 hr). Recovery of language/motor function is unlikely if no improvement within 2 weeks. Neurologic defi cits beyond 6 months usually persist.

If embolism is cardiogenic in origin, 10–15% develop a second embolus within 2 weeks.

Prognosis is good for recovery of function. Other lacunes frequently develop.

Prognosis depends on severity of hypotension. Most who eventually recover awaken by 72 hr. Adverse prognostic factors include dilated non-reactive pupils >12 hr and absent corneal, oculocephalic, oculovestibular refl exes.

OVERVIEW OF TREATMENT OF ISCHEMIC STROKE

Initial treatment of ischemic stroke depends on the type of stroke and eligibility for thrombolytic therapy (Figure 2.3). Measures to prevent recurrent stroke are based on the location/severity of the stenosis (Table 2.2) or the presumed embolic source (Table 2.3).

Table 2.1. Ischemic Stroke: Clinical Features (cont'd)



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1. Absence of intracranial or subarachnoid hemorrhage on CT or MRI and exclusion of nonvascular mimics (seizure with postictal neurologic defi cit, subdural hematoma, brain tumor, brain abscess, encephalitis, complicated migraine, glucose abnormalities).

2. Innominate, common carotid, internal carotid, vertebral, basilar, anterior cerebral, middle cerebral, or posterior cerebral arteries.

3. Less than 4.5 hours from symptom onset; no hemorrhage on CT scan; early infarct not more than 1/3 of MCA territory; no exclusion criteria (Table 3.1, p. 31). Although not approved for this indication, IV tPA may be considered beyond 3 hours. IA thrombolysis and the MERCI retrieval device are also options.

4. Total tPA dose, 0.9 mg/kg (max, 90 mg): 10% of total dose as IV bolus over 1 minute followed by remain-ing 90% as a constant IV infusion over 60 minute. Anticoagulants and antiplatelet agents are withheld for 24 hours.

5. Either aspirin 160–325 mg once daily, clopidogrel 75 mg once daily, or combination low-dose aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily, in patients not receiving heparin, starting within 48 hours of stroke onset. Cilostazole 100 mg bid has been shown to be effective in Asians. See discussion, pp. 102–109.

Figure 2.3. Evaluation and Treatment of Ischemic Stroke

Ischemic Stroke1

Suspected large arterythrombosis/stenosis2

Lytic-eligible3

tPA4 Antiplatelet5

or heparin6

Ultrasound with Doppler (neck andtranscranial; anterior and posterior

circulations) or MRA/CTA

Lytic-ineligible Lytic-eligible3

tPA4 Heparin6

EchocardiogramAmbulatory ECG monitoring

Definitive therapy based onpresumed embolic source

(e.g., arrhythmia, LV thrombus,valve disease; see pp. 22–24)

High-grade stenosis No high-grade stenosis

Cerebral angiography

Definitive therapy based on locationand severity of stenosis (see pp. 20–21)

Antiplatelet5

Lytic-ineligible

Lacunarstroke

Suspectedcardiogenic embolism

No anticoagulationEmpiric antiplatelet therapy

Control hypertension



6. Given the high risk of stroke progression or recurrence, it is reasonable to administer IV heparin acutely to lytic-ineligible patients if either: (1) vascular imaging or echocardiography identifi es a cardiac source of embolism or a recent occlusion/severe stenosis of a large extracranial or intracranial artery; or (2) a cardiac source of embolism or large artery atherothrombosis is suspected clinically, until vascular imag-ing and echocardiography are performed. All other lytic-ineligible patients and those with a contrain-dication to heparin (a large brain infarct is a relative contraindication) should be treated with aspirin 160–325 mg/d or another antiplatelet agent, starting within 48 hours of stroke onset. Unfractionated heparin should be given as an IV infusion (without bolus) starting at 800–1000 U/hr and adjusted to maintain the PTT at 1.5–2.5 times control until a mechanism of stroke is identifi ed and more defi nitive treatment is instituted. Low-molecular-weight heparin reduced mortality in one randomized trial (TOAST,p. 152) but is not yet approved for use in stroke in the U.S.

LYTIC-ELIGIBLE PATIENTS

When used in strict accordance with the NINDS tPA study protocol, IV administration of tPA increases the likelihood of minimal or no disability by approximately 30%. In carefully selected patients, the recent ECASS III study showed that patients treated with tPA 3–4.5 hours after symptom onset had a 15% better chance of a good functional outcome. (NOTE: tPA is not FDA approved beyond 3 hours) (see Chapter 14). Inclusion and exclusion criteria, baseline evaluation, dosing and administration guidelines, management of complications, and post-lytic measures are described in Chapter 3.

LYTIC-INELIGIBLE PATIENTS

Despite the effi cacy of thrombolytic therapy for acute ischemic stroke caused by large artery atherothrombosis or brain embolism, more than 95% of patients fail to meet eligibility criteria for thrombolysis, usually due to late presentation. For this large group of patients, therapy consists of antiplatelet agents or anticoagulants.

A. Antiplatelet Therapy. All lytic-ineligible patients not treated with IV heparin should receive antiplatelet therapy starting within 48 hours of symptom onset, unless there is an allergy to antiplatelet therapy or active bleeding. Recommended therapy consists of aspirin 160–325 mg once daily, clopidogrel 75 mg once daily, or combination low-dose aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily. Based on results from the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST) (p. 150), it has been estimated that for every 1000 acute strokes treated with early aspirin therapy, 9 deaths or nonfatal strokes are prevented in the fi rst few weeks and 13 fewer patients will be dead or dependent at 6 months.



B. Heparin Therapy 1. Clinical Trials. The use of heparin for acute ischemic stroke is controversial. In small

studies, heparin has been of benefi t in the setting of cardiac embolism (Stroke 1983; 14:668), but not for progressing stroke or crescendo TIAs. Two larger studies —one using subcutaneous heparin (IST, p. 151) and another using a synthetic IV heparinoid (TOAST, p. 152) —failed to demonstrate a benefi t for early anticoagulation. However, effi cacy was not evaluated by stroke mechanism in IST, and subgroups may not have been large enough to demonstrate benefi t for a given stroke mechanism in TOAST. In a more recent trial (Stroke 2005;36:2415–2420) 418 patients with nonlacunar stroke were randomized to IV heparin (to maintain PTT at 2–2.5 × control for 5 days). While there were more independent patients at the 90-day mark, there were also more symptomatic brain hemorrhages.

2. Recommendations. Given the high risk of stroke progression or recurrence, and until more data are available, it is reasonable to administer IV heparin acutely to lytic-ineligible patients with ischemic stroke if vascular imaging or echocardiography identifi es a cardiac source of embolism, recent atherothrombosis of a large extracranial or intracranial artery, or neck artery dissection. Heparin should also be considered for patients in whom a cardiac source of embolism or high-grade or complete large artery stenosis/occlusion is suspected clinically until vascular imaging and echocardiography are performed. A large brain infarct is a relative contraindication to heparin use.

3. Heparin Dose. Unfractionated heparin should be given as an IV infusion (without bolus) starting at 800–1000 U/hr and adjusted to maintain the PTT at 1.5–2.5 times control. Heparin is usually continued until the mechanism of stroke is identifi ed and more defi nitive treatment is instituted. Low-molecular-weight heparin reduced mortality in one randomized trial (p. 152) but is not yet approved for use in stroke in the U.S. for this indication.

MEASURES TO PREVENT RECURRENT STROKE

Following acute therapy with tPA or aspirin/heparin (lytic-ineligible patients), therapeutic measures are indicated to reduce the risk of recurrent ischemic stroke. For ischemic stroke caused by large artery atherothrombosis, preventive measures depend on the culprit vessel and stenosis severity (Table 2.2). For ischemic stroke caused by brain embolism, preventive measures depend on the source of embolism (Table 2.3).



Table 2.2. Therapeutic Measures to Prevent Recurrent Ischemic Stroke Due to Large Artery Atherothrombosis†

Internal Carotid Artery

Stenosis Therapy Comments

Total occlusion (100%)

Short-term heparin (PTT 1.5–2.5 � control) followed by warfarin (INR 2.0–3.0) � 6 weeks

Maintain blood pressure and volume status. Anticoagulant therapy may prevent clot propagation and embolization of fresh clot.

Severe stenosis (70–99%)

Urgent CEA‡. Otherwise, treat with long-term warfarin

CEA reduces stroke rate and improves survival. Timing of endarterectomy is controversial; early endarterectomy may prevent early recurrent infarct but is also associated with increased risk of reperfusion injury and ICH.

Plaque disease (50–69%)

Men: CEA‡ plus antiplatelet therapy.* Women: antiplatelet therapy*

NASCET II (p. 156) trial demonstrated benefi t of CEA in men with symptomatic 50–70% carotid stenosis. Antiplatelet therapy reduces vascular events by 20% following TIA or mild stroke (p. 157).

Stenosis <50% Antiplatelet therapy.* Also consider omega-3 oils (1 gm tid) and statins

Vertebral Artery

Total occlusion (100%)

Short-term heparin (PTT, 1.5–2.5 � control) followed by warfarin (INR, 2.0–3.0) � 3–6 weeks

Maintain blood pressure and volume status. Anticoagulation may prevent clot propagation and embolization of fresh clot.


Antiplatelet therapy or long-term warfarin. Surgery and balloon angioplasty/stenting have been successfully performed

Monitor stenosis noninvasively every 6 months. If total occlusion develops, continue anticoagulation for an additional 3–6 weeks to prevent propagation of clot in situ. The WASID-P study (New Engl J Med 352(13):1305–1316) found no benefi t to warfarin over high-dose aspirin in these patients.

†Therapeutic measures following acute reperfusion therapy with tPA or acute antithrombotic therapy with aspirin or heparin (see p. 19). Cardiovascular and cerebrovascular risk reduction measures are required for all patients (Chapters 9–14).

*Aspirin (81–325 mg/d), clopidogrel (75 mg/d), or combination low-dose aspirin plus extended- release dipyridamole (25 mg/200 mg bid). Consider combination aspirin (81–325 mg/d) plus clopidogrel (75 mg/d) for high-risk patients, especially those at increased risk of cardiac events. See discussion, pp. 102–109.‡Carotid stenting may be considered for high-risk patients.



Table 2.2. Therapeutic Measures to Prevent Recurrent Ischemic Stroke Due to Large Artery Atherothrombosis† (cont’d)

Vertebral Artery


Plaque disease (<70%) Antiplatelet therapy.* For symptomatic TIAs or mild stroke, platelet inhibitors may be more effective at reducing stroke and death in the vertebrobasilar circulation than in the carotid circulation (Lancet 1987;2:1351).

Intracranial Disease


Total occlusion (100%) Short-term warfarin (INR, 2.0–3.0) � 3–6 weeks.

Clinical manifestations depend on the culprit vessel (Figure 2.2):ACA: contralateral sensorimotor loss (leg > arm/face).PCA: hemianopia ± hemisensory loss. Basilar artery: bilateral weakness, cranial nerve paralysis.The WASID-P study failed to demonstrate benefi t of warfarin over aspirin for patients with symptomatic intracranial disease (stenosis 50–99%). Nonetheless, many vascular neurologists continue to use warfarin for high-grade basilar stenosis.


Aspirin or long-term warfarin (INR, 2.0–3.0). If occlusion develops on warfarin, continue anticoagulation for another 3 weeks, then switch to antiplatelet therapy.

Plaque disease (<50%) Antiplatelet therapy.*

†Therapeutic measures following acute reperfusion therapy with tPA or acute antithrombotic therapy with aspirin or heparin (see p. 19). Cardiovascular and cerebrovascular risk reduction measures are required for all patients (Chapters 9–14).

*Aspirin (81–325 mg/d), clopidogrel (75 mg/d), or combination low-dose aspirin plus extended- release dipyridamole (25 mg/200 mg bid). Consider combination aspirin (81–325 mg/d) plus clopidogrel (75 mg/d) for high-risk patients, especially those at increased risk of cardiac events. See discussion, pp. 102–109. For plaque disease, some studies suggest benefi t with lower-dose aspirin (81–162 mg/d).



Table 2.3. Therapeutic Measures to Prevent Recurrent Ischemic Stroke Due to Brain Embolism*

Source Therapy Comments

Atrial fi brillation • For acute embolism, consider tPA or intraarterial thrombolysis with tPA or urokinase (experimental), depending on the presence/location of occlusive embolus.

• For primary and secondary prevention, treat with warfarin (INR, 2.0–3.0) as long as AF persists. Aspirin or another antiplatelet agent may be considered for primary prevention of embolic stroke in patients <60 years old with “lone” AF (i.e., no history of hypertension, heart disease, or prior embolism).

Incidence of systemic embolization is 5–6% per year, and most embolic events are cerebral. Warfarin reduces stroke by up to 80% and improves survival in nonvalvular AF (pp. 142–144).Hemorrhagic transformation occurs in 20–30% of embolic strokes; therefore, some initiate anticoagulation only if a CT/MRI at day 3–5 is negative for hemorrhage, especially if the area of infarction is large. Even if hemorrhagic transformation occurs, it is usually well tolerated (exception: symptomatic hemorrhage with tPA).

Acute myocardial infarction

For primary prevention of stroke, consider warfarin (INR, 2.0–3.0) � 3–6 months for acute MI complicated by ventricular aneurysm, mural thrombus (especially if large or pedunculated), or a large area of hypokinesis.

The incidence of systemic embolization following anterior MI and inferior MI is 6% and 1%, respectively, and most embolic events are cerebral. The risk of embolization is highest for protruding LV thrombus, especially in the fi rst few months after MI. Acute stroke during thrombolytic therapy for acute MI is often hemorrhagic and may require drainage of hematoma.

Valvular heart disease

• For primary prevention of stroke, no specifi c therapy is recommended for native valve disease with sinus rhythm.

• For mechanical prosthetic valves, treat with warfarin (INR, 3.0–4.5) long term.

The risk of embolization in patients with rheumatic mitral stenosis and AF is increased 17- fold compared to patients without valve disease in sinus rhythm. Embolization rates for mechanical mitral valves, mechanical aortic valves, and bioprosthetic valves are 4%, 2%, and 1% per year, respectively.



Table 2.3. Therapeutic Measures to Prevent Recurrent Ischemic Stroke Due to Brain Embolism* (cont'd)


• For prevention of recurrent stroke, treat with warfarin for native valve disease (INR 2.0–3.0) and prosthetic valves (INR, 3.0–4.5).

• For embolization despite warfarin, options include intensifi cation of warfarin therapy, addition of low-dose aspirin (81–165 mg/d) or possibly other antiplatelet agents, or valve surgery.

Cardiomyopathy In a retrospective trial of patients with ejection fractions <20% and heart failure, warfarin decreased the rate of cardiac embolization compared to aspirin (J Am Coll Cardiol 1993;21:218 A). Prospective trials are needed to confi rm this fi nding.

The source of emboli is usually LV mural thrombus, which develops as a result of poor systolic function and blood stasis.

Atrial myxoma Surgical excision is indicated for the prevention of recurrent stroke.

Atrial myxoma is the most common primary cardiac tumor and can mimic mitral valve disease (stenosis/regurgitation) or infectious endocarditis.

Paradoxical embolism For prevention of recurrent stroke, warfarin is indicated if the patient has a proven venous clot; studies have shown that patients with ASD and PFO are at higher risk, but neither warfarin nor surgical closure has been shown to be more effective than antiplatelet agents.

ASD and PFO are the most common routes for paradoxic embolus. Contrast echo with Valsalva maneuver, which can visualize interatrial communications, is recommended for all young patients with unexplained stroke. Paradoxic embolism can also occur in older age groups.




Other cardiac conditions

• Aspirin (325 mg/d) is indicated for the prevention of recurrent embolic stroke due to mitral valve prolapse, mitral annular calcifi cation, calcifi ed aortic valve, or marantic endocarditis. For recurrences on aspirin, consider long-term warfarin.

• For emboli due to infectious endocarditis, treat with antibiotics. Anticoagulation does not prevent embolization and increases the risk of bleeding from a mycotic aneurysm or cerebral embolus.

Marantic endocarditis (nonbacterial thrombotic endocarditis) is a common cause of stroke in patients with cancer or other chronic debilitating illnesses. Marantic vegetations and vegetations in patients with systemic lupus erythematosus or antiphospholipid antibody syndrome consist of friable platelet-fi brin nodules, usually along the valve commissures. A single embolus is not an indication for valve surgery in infectious endocarditis, but valve replacement should be considered for recurrent emboli despite appropriate antimicrobial therapy. Embolization rate after 24 hr of antibiotic control is low (<5%).

*Cardiovascular and cerebrovascular risk-reduction measures are required for all patients.

LACUNAR STROKE

Lacunar stroke accounts for 15–20% of ischemic strokes and is caused by atherothrombotic or lipohyalinotic occlusion of one of the small penetrating branches of the circle of Willis, MCA, or vertebral/basilar arteries. Occlusion results in a small infarct of the deep brain structures (basal ganglia, cerebral white matter, thalamus, pons, cerebellum), ranging in size from 3 mm to 2 cm. Risk factors include hypertension, diabetes, and polycythemia. The neurologic defi cit of lacunar infarction is typically fl uctuating, stepwise progressive, or remitting, and gradually worsens over days. Patients are usually alert without headache or vomiting. Lacunar stroke is preceded by TIAs in 25% of cases and presents as one of several well-defi ned syndromes, including: pure motor hemiparesis (contralateral hemiparesis; dysarthria; no sensory or visual loss or cognitive impair-ment); pure sensory stroke (contralateral sensory loss or paresthesias; no motor loss, dysarthria, visual loss, or cognitive impairment); dysarthria-clumsy-hand syndrome (dysarthria, dysphagia, weakness of contralateral face and tongue, paresis and clumsiness of contralateral arm and hand); ataxic hemiparesis (prominent ataxia of contralateral leg and arm; paresis of contralateral leg and side of face); isolated motor/sensory stroke (paresis or sensory loss of contralateral leg,

Table 2.3. Therapeutic Measures to Prevent Recurrent Ischemic Stroke Due to Brain Embolism* (cont'd)



arm, or face; no visual loss or cognitive impairment). Management includes long-term control of blood pressure and empiric antiplatelet therapy. Omega-3 oils (1 gm tid) can be used to decrease whole blood viscosity and possibly improve blood fl ow through narrowed penetrat-ing arteries. Some experts argue that lacunar stroke should not be treated with thrombolytics; despite claims by the authors that lacunar infarct patients fared better when treated with tPA in the NINDS trial, a blue-ribbon committee that reviewed the data concluded that the stroke subtype conclusions were invalid (Stroke 2004;35:2418–2424).

No study has determined the effectiveness of lytic therapy in patients with lacunar infarcts or in those with no demonstratable large artery occlusions. Prognosis is good for recovery of function, although other lacunes frequently develop.

TRANSIENT ISCHEMIC ATTACK

TIAs are brief episodes of neurologic dysfunction caused by reversible ischemia in a vascular territory. The term “TIA” is used to encompass episodes lasting less than 24 hours; however, most TIAs last less than 1 hour, and the majority of vascular neurologic symptoms that persist for more than 1 hour are unlikely to fully resolve. Patients with transient symptoms often develop ischemic lesions on brain imaging, blurring the distinction between TIA and stroke. The mechanisms, workup, and treatment of TIA are the same as for ischemic stroke. Patients with TIA are at high risk for developing stroke in the short term; in a study of >1700 patients with TIA, 5% had a stroke within 48 hours, and 10% had a stroke within 90 days (JAMA 2000;284:2901–2906).



Chapter 3

Thrombolytic Therapy for Acute Ischemic Stroke


OVERVIEW

The rationale for thrombolytic therapy with rt-PA, which activates plasminogen to degrade thrombus via breakdown of fi brin ( Figure 3.1), is based on studies demonstrating that 80% of ischemic strokes are caused by occlusive clot and that neuro nal death and brain infarction are time-dependent events (Stroke 2003;34:1056–1083). In early observational studies, acute stroke patients were screened clinically and by CT, and then angiography was performed. If an intracranial arterial occlusion was shown, thrombolytic drugs were given either IA into the clots, or IV. Follow-up angiography was performed after treatment to assess recanalization. Both anterior and posterior circulation thromboembolism were treated. The results of these early studies were not included in the publications of the results of the later randomized trials. In all of these early angiographic studies, and in angiographically controlled trials since release of rt-PA, recanalization heavily correlates with outcome. As far as is known, thrombolytic agents act only by lysing clots. If arteries are not opened, the drugs do not facilitate recovery. Knowing the recanalization rate of agents given IV and IA in patients with various occlusive arterial lesions is extremely helpful in choosing appropriate therapy. IV tPA was seldom effective in patients with occlusion of the ICA in the neck or intracranially and often was not effective when the proximal MCA was occluded. Branch MCA lesions often recanalized after IV tPA.

A. When used in strict accordance with the NINDS tPA study protocol, IV administration of tPA within 3 hours of stroke onset increases the likelihood of minimal or no disability by 30% or more. To be maximally effective, tPA should be administered as early as possible. Analyses of tPA effi cacy by time show that patients treated earlier (e.g., within the fi rst 90 minutes of the 3-hour window) do better than those treated later. The recent ECASS III study shows that tPA administration within 4.5 hours of symptom onset was safe and effective. However, such treatment should carefully consider the risk/benefi t. For patients presenting with MCA infarction within 6 hours of stroke onset, intraarterial thrombolysis using pro-urokinase has been shown to improve outcome at 90 days in the PROACT II trial (p. 155). Because pro-urokinase is not available in the U.S., intraarterial tPA is being used in a similar fashion at select sites with interventional neuroradiologic capability. Intraarterial thrombolysis may improve recanalization rates, but time delay to onset of therapy has been an important limitation of this approach. The MERCI retrieval device has been FDA approved since 2005 and is another option for patients with large artery clot; the MERCI retriever can be used within 8 hours of symptom onset. Multiple newer thrombolytic and antiplatelet agents



have been used in clinical trials, including retaplase (Neurosurgery 2001;49:41–50), desmoteplase (Lancet Neurology 2009;8:141–150), abciximab (Stroke 2000;31:601–609; AbESST trials, pp. 149–150), and the combination of abciximab or integrelin with tPA or retaplase (Neurology 2001;56:1585–1587; Stroke 2002;33:359). None is FDA approved, and positive effi cacy data are scant. These agents should not be used outside of clinical trials. Thrombectomy, laser, ultrasound devices, and balloon angioplasty/stenting in conjunction with antiplatelet, antithrombin, and thrombolytic therapy are under investigation.

Plasminogen

PlasminPAl-1

tPA

�2-antiplasmin (2)

D-polymers and D-dimers

Fibrin degradation products

(2)(1)

FibrinClot

Figure 3.1. Thrombolytic Therapy and Dissolution of Clot

PAI-1 = plasminogen activator inhibitor. Thrombolytic agents activate plasminogen, which degrades throm-bus via breakdown of fi brin. Fibrin breakdown results in the release of fi brin degradation products (D-dimers and other D-polymers).

Chapter 3. Thrombolytic Therapy for Acute Ischemic Stroke 29


B. The use of IV and IA tPA, combined with ultrasound-aided catheter thrombolysis, is being studied in the Interventional Management of Stroke (IMS) Trials. Data from IMS I and II, which are open label and unrandomized (see Chapter 15) shows superior results for this approach compared to IV tPA, with similar complication rates. A randomized trial (IMS III), with IV tPA as the control group, is now underway. Thrombolytic therapy represents a major advance in the treatment of acute ischemic stroke but is now only applicable to 2–5% of patients, primarily due to delays in hospital presentation and inability at many hospitals to provide rapid assessment and treatment. Efforts to teach individuals to recognize the symptoms of stroke and the need to seek immediate medical attention will increase the utilization of thrombolytic therapy. Secondary prevention measures can reduce the risk of recurrent stroke by more than 50% and are mandatory for all patients (Chapters 9–14).

C. Baseline Evaluation. Inclusion and exclusion criteria for thrombolytic therapy are shown in Table 3.1. Ideal candidates have no hemorrhage on CT scan and NIH stroke scores of 4–20 (i.e., moderate defi cit) (Table 3.2). Patients with scores ≤4 (no or very mild defi cit) have a very good prognosis and may not benefi t from tPA, while patients with scores >20 (severe defi cit) are at increased risk of ICH; individualization of therapy based on an estimate of the risk/benefi t ratio is required in these cases. Baseline laboratory evaluation in lytic-eligible patients includes fi brinogen, hemoglobin, hematocrit, PT/PTT, and platelet count; type and cross 4 units of packed red blood cells is also recommended.

D. Dosing and Administration of Thrombolytic Therapy. tPA is given at a total dose of 0.9 mg/kg (max, 90 mg): 10% of the total dose is given as an IV bolus over 1 minute, and the remaining 90% is administered as a constant IV infusion over 60 minutes. Anticoagulants and antiplatelets are withheld for the next 24 hours. For suspected cardiogenic embolism or large vessel atherothrombosis, heparin is often started 24 hours after lytic therapy as an IV infusion (without bolus) of 800–1000 U/hr and adjusted to a PTT of 1.5–2.5 times control until the diagnostic evaluation is complete and defi nitive therapy is instituted. Antihypertensive therapy is administered as needed to maintain blood pressure <180/105 mmHg.

E. Post-Lytic Care 1. General Measures. Following thrombolytic therapy, vital signs and neurologic

status should be checked every 15 minutes for the fi rst 2 hours, every 30 minutes × 6 hours, then hourly × 18 hours. To minimize the risk of ICH, blood pressure should be maintained <180/105 mmHg and antiplatelet and anticoagulant therapy should be withheld for 24 hours. Blood draws and invasive lines/procedures should also be avoided for 24 hours after thrombolysis, if possible.



Inclusion Criteria

Stroke onset <4.5 hours. Time of onset is the time when the patient was last known to be • normal. If time of onset is uncertain, tPA should not be given, with the possible exception that diffusion/perfusion MRI and MRA show a vascular occlusion with no or minor brain infarction and a large area of brain tissue that is underperfused but not yet infarcted. tPA is approved only for IV administration within 3 hours of stroke onsetNo hemorrhage on CT scan• Early infarct not >1/3 of MCA territory• Screening NIH stroke score (Table 3.2). Ideal candidates for thrombolytic therapy have • scores of 4–20 (mild to moderate defi cit). Patients with scores £4 (no or very mild defi cit) have a very good prognosis and may not benefi t from tPA; however, if patients’ scores are disabling (examples: an isolated, severe aphasia would yield an NIH stroke scale score of 2–3, or a leg monoplegia which would leave a patient unable to ambulate), treatment should be strongly considered. Patients with scores >20 (severe defi cit) are at increased risk of ICH; individualized therapy based on an estimate of the risk/benefi t ratio is required in these cases

Exclusion Criteria

Active bleeding• SBP >185 mmHg or DBP >110 mmHg• Aggressive treatment required to reduce blood pressure to specifi ed limits• Symptoms of SAH• Prior ICH felt by examiner to predispose patient to high risk of recurrence• Stroke or head trauma within 3 months• MI within 3 months• Major surgery or other serious trauma within 2 weeks• GI or urinary tract hemorrhage within 21 days• Arterial puncture at a noncompressible site within 7 days• Taking anticoagulants or receiving heparin within 48 hours• INR >1.7 or elevated PTT• Platelet count <100,000/mm• 3

Glucose <50 mg/dL or >400 mg/dL• Pregnancy or lactation• Relative exclusions• Seizures not thought to be related to an acute stroke•

• Rapidly improving or minor defi cit. However, many of these patients, especially those with vascular imaging that shows an occlusive thromboembolus, go on to develop severe neurologic defi cits. If vascular imaging is available in this group of patients, we strongly recommend its useAdditional exclusions for patients in a 3–4.5-hour window (based on ECASS III study): • Age >80, patients taking anticoagulants, patients with an NIHSS score of >25, and patients with both diabetes and a history of prior stroke.

Table 3.1. Thrombolytic Therapy for Acute Ischemic Stroke: Inclusion and Exclusion Criteria



2. Management of Elevated Blood Pressure a. SBP >180 mmHg or DBP >105 mmHg on two consecutive readings 5–10 minutes apart. Consider treatment with labetalol 10 mg IV over 1–2 minutes. The dose can be repeated or doubled every 10–20 minutes up to a total cumulative dose of 300 mg. If a satisfactory response is not obtained, nitroprusside can be administered at a dose of 0.5–10 mcg/kg/min. Nicardipine (5 mg/hr IV infusion as initial dose and titrate to desired effect by increasing 2.5 mg/hr every 5 minutes to maximum of 15 mg/hr) is another option. BP should be monitored every 10 minutes during IV therapy, and the patient should be observed for hypotension. (If SBP >230 mmHg or DBP = 121–140 mmHg and labetalol is contraindicated, consider enalapril 1.25–2.5 mg IV every 6 hours.)

b. DBP >140 mmHg. Treatment with IV sodium nitroprusside at 0.5–10 mcg/kg/min is recommended. Nicardipine (5 mg/hr IV infusion as initial dose and titrate to desired effect by increasing 2.5 mg/hr every 5 minutes to maximum of 15 mg/hr) is another option. BP should be monitored every 10 minutes during IV therapy, and the patient should be observed for hypotension.

F. Management of Lytic Complications. If acute deterioration in neurologic status develops during tPA infusion, ICH should be suspected. In this situation it is important to immediately discontinue the tPA infusion and obtain an emergency unenhanced head CT to confi rm the diagnosis. For life-threatening hemorrhage, urgent treatment includes transfusion of 6–8 units of platelets and 4–6 units of cryoprecipitate. Aminocaproic acid should also be given at a dose of 4–5 gm IV over 1 hour followed by 1 gm PO or IV push hourly until bleeding is controlled. Fibrinogen levels should be rechecked every 4 hours and cryoprecipitate transfused as needed to maintain fi brinogen levels >150 mg/dL. Periodic CBC and PT/PTT measurements should also be obtained. If blood transfusion is required, the patient should be typed and crossmatched for 4 units of packed red blood cells, 4–6 units of cryoprecipitate or fresh frozen plasma, and 1 unit of single-donor platelets.



ITEM AND RESPONSE (Score) ITEM AND RESPONSE (Score)

1a. Level of consciousness alert (0) drowsy (1) stuporous (2) coma (3)

1b. Response to level-of-consciousness questions* answers both correctly (0) answes one correctly (1) answers neither correctly (2)

1c. Response to level-of-consciousness commands † obeys both corrrectly (0) obeys one corectly (1) obeys neither (2)

2. Best gaze normal (0) partial gaze palsy (1) total gaze palsy (2)

3. Visual fi elds no visual loss (0) partial hemianopia (1) complete hemianopia (2)

4. Facial palsy normal (0) mild paralysis (1) partial paralysis (2) complete paralysis (3)

5. Motor arma. leftb. right no drift (0) drifts but does not fully drop (1) resists gravity but falls before 10 sec (2) no effort against gravity (3) no movement (4)

6. Motor lega. leftb. right no drift (0) drifts but does not fully drop (1) resists gravity but falls before 5 sec (2) no effort against gravity (3) no movement (4)

7. Ataxia absent (0) one limb (1) two limbs (2)

8. Sensory normal (0) mild loss (1) severe loss (2)

9. Language normal (0) mild aphasia (1) severe aphasia (2)

10. Dysarthria normal (0) mild (1) severe (2)

11. Extinction/inattention normal (0) mild (1) severe (2)

* Level-of-consciousness questions: “How old are you?” “What month is this?”† Level-of-consciousness commands: “Squeeze my hand” (using nonparetic hand), “Close your eyes.”

Adapted from: The National Institutes of Health Stroke Scale. NINDS.

Table 3.2. National Institutes of Health Stroke Scale (maximum score = 42)



Chapter 4

Brain Hemorrhage


Hemorrhagic stroke can be readily classifi ed into SAH, ICH, and subdural/extradural hemorrhage based on clinical presentation and CT scan (Table 4.1).• Subarachnoid hemorrhage presents with sudden-onset severe headache, cessation

of activities, and vomiting without focal neurologic signs. CT scan shows blood in the subarachnoid space and brain cisterns, and spinal fl uid is always bloody.

• Intracerebral hemorrhage presents with focal neurologic symptoms. Headache, vomiting, and decreased consciousness often accompany larger hemorrhages. CT and MRI show a hematoma within the brain.

• Subdural and extradural hemorrhage are usually caused by head trauma. Lesions are outside the brain, either inside (subdural) or outside (extradural) the dura mater.

Depending on the type and cause of brain hemorrhage, management includes prevention of rebleeding and vasospasm; correction of bleeding diatheses; control of hypertension; lowering of increased ICP; surgical clipping, ligation, or coating of ruptured aneurysms; excision of AVMs and cavernous angiomas; and drainage of hematomas.

Table 4.1. Hemorrhagic Stroke: Clinical Features

Subarachnoid Hemorrhage

Intracerebral Hemorrhage

Subdural/Epidural Hematoma

Risk factors Hypertension, bleeding disorders, drugs, trauma. Often occurs in absence of risk factors.

Hypertension, bleeding disorders, amyloid angiopathy, drugs (amphetamines, cocaine), trauma.

Old age, falls, head injury, anticoagulants.

Onset of neurologic defi cit

Sudden, typically during exertion. Warning leak occurs in 15–30% as a headache (“sentinel headache”) that often goes unrecognized. Focal neurologic signs may be absent or manifest as subtle hemiparesis or oculomotor nerve palsies.

Symptoms gradually progress over minutes to hours. Occasional onset with exertion or stress. Focal neurologic defi cit is prominent and suggests location of hemorrhage.

Gradual (usually slight) weakness and numbness on one side.






Associated symptoms

Sudden onset of severe headache, cessation of activity, vomiting, nuchal rigidity. Initial loss of consciousness, seizures, confusion, agitation, photophobia ± phonophobia.

Headache, vomiting, decreased consciousness, seizures, especially with large bleed. Headache may be absent in 50%, especially with smaller bleed.

Headache, diminished alertness.

Stroke location Subarachnoid, occasionally meningocerebral.

Most commonly deep brain structures (basal ganglia, cerebral white matter, thalamus, pons, cerebellum), although any part of the brain can be affected.

Extracerebral blood; most commonly cerebral convexities.

Imaging CT: hyperdensity (bright) MRI: dark (Tl -weighted images); bright (T2-weighted images). Location in subarachnoid space. MRI may be less sensitive than CT scan for detection of subarachnoid blood.

CT: focal hyperdensity (bright) MRI: acute (<24 hrs) (dark on T1 images; bright on T2 images); subacute (1–5 days) (dark on T1/T2 images); chronic (months) (bright on T1/T2 images). Location within brain parenchyma, often spreading to surface and/or ventricles. Dark on T2*-weighted images.

CT: hyperdensity (bright) over convexity of brain. MRI: abnormal signal in subdural/ epidural space.

Treatment Clipping or coiling of berry aneurysms (early) and AVMs (late). Prevention of rebleeding/vasospasm; control of ICP.

Control of hypertension, increased ICP, bleeding diathesis. Surgical drainage of large putaminal, lobar, cerebellar hematomas.

Surgical drainage if large.

Table 4.1. Hemorrhagic Stroke: Clinical Features (cont’d)

Chapter 4. Brain Hemorrhage 37





Prognosis Ruptured aneurysm: High morbidity and mortality. Early re-bleed with vasospasm and cerebral infarction are common. Overall, 33% of patients die before reaching the hospital, 20% die in the hospital or have severe disability, 17% deteriorate in the hospital, and only 30% do well. Rebleed rate is 3% per year in patients without surgery Ruptured AV malformation: Better prognosis than after ruptured aneurysm. Early rebleed/vasospasm uncommon. Mortality with fi rst hemorrhage is 10%. Rebleed rate is 0.5–2% per year with 20% mortality.

Size of bleed determines outcome. One-month mortality is 30%. The probability of signifi cant functional recovery is greater following ICH (tissue is pushed aside) than following cerebral infarction (tissue is rendered necrotic due to ischemia).

Excellent if drained before brain herniation.

SUBARACHNOID HEMORRHAGE

A. Ruptured Saccular (Berry) Aneurysm 1. Overview. Ruptured berry aneurysms are responsible for 80% of SAHs. The vast

majority (>90%) of berry aneurysms originate from the anterior circle of Willis, and those that rupture are usually >5 mm in diameter. Patients are usually asymptomatic prior to rupture, although 15–30% have a warning leak, manifest as a headache (“sentinel headache”) that often goes unrecognized. The onset of neurologic defi cit—severe headache, cessation of activity, vomiting, stiff neck—is sudden and typically occurs during exertion. Most patients present without focal neurologic defi cit, although a third-nerve palsy (aneurysm of the posterior communicating artery), hemiparesis and aphasia (MCA aneurysm), or paraparesis and encephalopathy (ACA aneurysm) may occur. Patients can also awaken with headache, confusion, stiff neck, and high

Table 4.1. Hemorrhagic Stroke: Clinical Features (cont’d)



fever. Conditions associated with berry aneurysm include coarctation of the aorta, fi bromuscular dysplasia, polycystic kidney disease, Marfan syndrome, Ehlers-Danlos, hereditary hemorrhagic telangectasia, neurofi bromatosis, and pseudoxanthoma elasti cum. Hypertension, bleeding disorders, and trauma increase the risk of SAH, but SAH often occurs in the absence of risk factors. The diagnosis of ruptured aneurysm is made by CT scan, which is 85–95% sensitive. If a CT scan is negative and the index of suspicion is high, an LP should be performed; a normal LP excludes the diagnosis of SAH. Angiography may at fi rst fail to identify the site of bleeding because of vasospasm. In these cases, angiography should be repeated at 2 weeks. Morbidity and mortality rates are high, and early rebleeding and vasospasm with cerebral infarction are common. Overall, 33% of patients die before reaching the hospital, 20% die in the hospital or have signifi cant disability, 17% deteriorate in the hospital, and only 30% do well. Rebleeding occurs in 3% of patients without surgery.

2. Treatment. Treatment of SAH includes bed rest in a dark, quiet setting, gentle hydration, and prophylactic anticonvulsant therapy (e.g., phenytoin 300–400 mg/d in divided doses to maintain plasma levels at 10–20 mcg/mL). Four-vessel angiography is recommended in all patients, and surgical clipping, coiling, or ligation is performed to reduce rebleeding and improve survival. A randomized trial (ISAT, p. 159) found that patients treated with endovascular coils had improved outcomes, as compared to those treated with clipping. Embolization or coiling of ruptured aneurysms may be indicated when the aneurysm is relatively inaccessible (e.g., basilar) or the patient is a poor operative risk. Surgery is warranted as soon as possible (within 72 hours) for patients who are alert, oriented, and have no focal defi cit (Hunt and Hess Class I or II) (J Neurosurg 1968;28:14). For the remaining patients, surgical intervention is performed at 10–14 days. Nimodipine is recommended to reduce the risk of vasospasm, which complicates 25–35% of SAHs and often results in cerebral infarction. The dose of nimodipine is 60 mg (PO) q 4 hours × 21 days (BMJ 1989;298:636).

B. Ruptured AVM 1. Overview. Ruptured AVMs account for 10% of SAHs. AVMs typically present as SAHs

(45%), seizures (35%), or progressive neurologic defi cits (20%); patients sometimes present with chronic, migraine-like headaches. Pregnant females with AVMs are at increased risk of SAH, especially during the fi rst trimester of pregnancy and during labor. The diagnosis of ruptured AVM is made by MRA and angiography. Prognosis is better than for ruptured aneurysm; mortality rates are 10% with the fi rst bleed and 20% with a second bleed. Early vasospasm and rebleeding are uncommon, and the rate of rebleeding is 0.5–2% per year.

2. Treatment. Younger patients with good neurologic function are treated by delayed surgical excision. Adjunctive embolization may also be considered in certain cases. For elderly patients and those with severe neurologic defi cit, radiation therapy or embolization may be appropriate. Patients with seizures without SAH may be treated with anticonvulsant therapy without surgery.



C. Complications of Subarachnoid Hemorrhage 1. Rebleeding. Without early surgical treatment, many ruptured berry aneurysms

rebleed—20% within 2 weeks, 30% within 1 month, 40% within 6 months—and rebleeding is associated with a mortality rate of 40%. Rebleeding typically presents as sudden severe headache, meningismus, and rapid development of coma; focal neurologic signs indicate the presence of intraparenchymal hemorrhage or vasospasm. Prevention is the key to therapy: adequate analgesia, control of hypertension, sedation, laxatives, and early surgery reduce the risk of rebleeding. In contrast to berry aneurysms, acute rebleeding is uncommon after ruptured AVM.

2. Vasospasm. Symptomatic vasospasm complicates 25–35% of ruptured berry aneurysms, usually between days 4 and 14, and most episodes result in cerebral infarction. Vasospasm typically presents as decreased level of alertness with or without hypertension and ECG changes; focal neurologic signs may also be present. Treatment consists of hypervolemic hemodilution (3 L/d) to decrease blood viscosity and maintain cerebral blood fl ow. Endovascular treatments, including IA vasorelaxants (such as papaverine or calcium-channel blockers), and/or angioplasty, should be considered for patients who are unresponsive to hypervolemic hemodilution. Early (within 10 days) administration of the calcium antagonist nimodipine reduces the risk of death or dependency within 3 months of aneurysmal SAH by 24% (Neurology 1998;50:876–883). The dose of nimodipine is 60 mg (PO) q 4 hours × 21 days.

3. Increased intracranial pressure (see pp. 46–47).

4. Hydrocephalus. Hydrocephalus can be acute or subacute (2–4 weeks) and manifests as increasing headache, lethargy, incontinence, and decreased spontaneity. The diagnosis is confi rmed by CT scan or MRI. Treatment consists of surgical (ventricular) drainage or repeat LPs.

5. Intracerebral hematoma. Surgical evacuation is often performed for hematomas that result in mass effect.

6. Cardiac. ECG abnormalities occur in more than 50% of patients after SAH and can persist for days. ECG changes can mimic acute myocardial infarction/ischemia and include long QT interval, ST segment elevation or depression, giant upright or inverted T waves, and prominent U waves. Arrhythmias are common following SAH and include sinus tachycardia, sinus bradycardia, tachy-brady syndrome, wandering atrial pacemaker, and AV junctional rhythm. Ventricular tachycardia occurs infrequently. Patients should be on continuous telemetry; malignant arrhythmias or arrhythmias leading to hemodynamic instability should be treated.

7. Hyponatremia. Hyponatremia may be due to the SiADH and is associated with a poor prognosis. This can be managed with fl uid restriction or hypertonic saline.



INTRACEREBRAL HEMORRHAGE

ICH usually results from an acute rise in blood pressure and primarily involves the deep brain structures, including the basal ganglia, cerebral white matter, thalamus, pons, and cerebellum. Other causes of ICH include bleeding disorders, amyloid angiopathy, drugs (amphetamines, cocaine), and trauma. Most patients present with a focal neurologic defi cit, which suggests the location of hemorrhage, and symptoms gradually progress over minutes to hours. Large bleeds are accompanied by headaches, vomiting, decreased consciousness, and seizures. In contrast, headache may be absent in 50% of smaller bleeds. On CT scan, ICH presents as a focal hyperdensity (bright); on MRI, acute hematomas are dark and chronic hematomas are white on T1- and T2-weighted images. Treatment consists of control of hypertension and increased ICP, correction of bleeding diatheses, and surgical drainage of large putaminal, lobar, or cerebellar hematomas. Prognosis depends on the size of the bleed and the patient’s clinical status. Overall, 1-month mortality is 30%. The probability of signifi cant functional recovery is greater following ICH than following cerebral infarction, as brain tissue is more likely to be pushed aside (bleed) than rendered necrotic (ischemic infarction). While an initial recombinant Factor VII study showed promise for a novel therapy for this condition, a follow-up study (see Chapter 15) showed no overall clinical benefi t despite a reduction in progression of bleeding. A group of patients with relatively small hemorrhages treated very early did benefi t.

A. Hypertension. Many intracerebral bleeds result from an acute rise in BP, which causes rupture of a normal, microaneurysmal, or lipohyalinotic segment of a small resistance artery. Elderly patients are at increased risk and can develop hemorrhage at lower blood pressures than do younger individuals. Papilledema may lag behind clinical improvement and is not necessarily a sign of worsening. Rebleeding at the same site does not usually occur. The goal of therapy is to lower SBP to ≤160 mmHg (10–20% reduction over the fi rst hour followed by more gradual reduction over the next 12–24 hours). Nitroprusside or labetalol is often used for this purpose. IV ACE inhibitors or nicardipine may also be used. Since the acute phase of stroke is associated with impaired cerebral autoregulation, marked reductions in BP may induce cerebral hypoperfusion. Therefore, if neurologic function deteriorates during antihypertensive therapy, drug dosage should be reduced or discontinued. In addition to controlling BP, it is important to reduce elevated ICP and to consider surgical drainage of large putaminal, lobar, or cerebellar hematomas. While the STICH study (Lancet 2005;365:387–397; discussed on page 171) did not fi nd benefi t to surgical intervention in supratentorial hematomas, surgery should be considered on a case-by-case basis for patients with superfi cial hematomas or with rapid clinical deterioration.



B. Other Causes of ICH. In addition to an acute rise in BP, ICH may occur as a result of ruptured AVM, amyloid angiopathy, bleeding diathesis, trauma, or hemorrhage into an infarct or tumor. ICH caused by illicit drug use (amphetamines, cocaine) usually occurs within a few minutes of exposure and manifests as headache, confusion, and seizures; mortality rates are high (20–30%). Depending on the cause, treatment varies from surgical excision of AVMs to reversal of bleeding diatheses. For ICH that develops during anticoagulation or thrombolytic therapy, restoration of normal clotting function is imperative. For patients receiving warfarin, the drug should be immediately discontinued and 2–3 units of fresh frozen plasma IV (or 5–25 mg vitamin K) should be administered. The PT should be checked in 6 hours and fresh frozen plasma transfused as needed to restore clotting function. For patients receiving heparin, the heparin infusion should be discontinued and protamine sulfate 20–30 mg (IV infusion) considered. For patients receiving a thrombolytic, the drug should be immediately discontinued and 6 units of cryoprecipitate given IV to increase the fi brinogen level to >150 mg/dL. Fibrinogen levels should be rechecked in 4–6 hours and cryoprecipitate transfused as needed.

C. Cerebellar Hemorrhage. Ten percent of ICHs occur within the cerebellum. Symptoms include inability to walk, vomiting, and headache; patients are usually alert at onset. Large bleeds often result in brainstem compression, which manifests as increasing stupor, lateral gaze palsy (toward hematoma), and a bilateral extensor plantar response. More than 75% of those awake at presentation progress to coma, which may be complicated by hypotension and respiratory depression. Surgical drainage is indicated for hemorrhage >3 cm in diameter, especially when accompanied by decreased consciousness. These patients often do quite well, with minimal long-term neurologic dysfunction.

D. Subdural and Extradural Hematoma. Most subdural hematomas are caused by laceration of bridging or cortical veins as a result of head trauma. Depending on the acuity and size of the hematoma, symptoms range from rapid deterioration in mental status and alertness to gradual, subtle weakness and numbness on one side. The diagnosis is made by CT scan. Treatment consists of surgical drainage of large hematomas and reversal of coagulation abnormalities.

• Acute subdural hematomas usually occur after trauma or rapid deceleration. Mortality rates for patients with severe head injuries are high (40–50%), and many survivors will have permanent neurologic defi cits.

• Subacute subdural hematomas develop 2 days to 1 week after head injury and can also occur with chronic anticoagulant therapy. They are usually less severe than acute subdural hematomas, and the prognosis is good.



• Chronic subdural hematomas present with confusion, morning headache, unsteadiness and/or weakness 1–6 weeks after head injury, which may not be remembered by the patient. Bilateral hematomas are sometimes present.

• Extradural hematomas typically present with abrupt, persistent loss of consciousness. The classic history of transient loss of consciousness followed by a lucid interval and then rapid deterioration is uncommon. Extradural hematomas are often associated with skull fractures that tear the middle meningeal artery. Because the ruptured vessel is arterial (and thus under higher pressure), hematomas can expand rapidly and lead to brain herniation and death. Correction of coagulation abnormalities and emergent surgical evacuation are warranted.



Chapter 5

Stroke-Related Complications


Patients with stroke are at high risk for serious medical complications caused by atherosclerosis (myocardial ischemia/infarction), prolonged bed rest and immobility (decubitus ulcer, DVT, pulmonary embolism, depression, malnutrition), and as a direct consequence of the stroke itself (increased ICP, seizures, stress-induced GI ulcers, urinary voiding problems, aspiration pneumonia). Major bleeding complications can also occur from the use of anticoagulants and thrombolytics. The prevention and treatment of stroke-related complications are described in Table 5.1.

Table 5.1. Treatment of Stroke-Related Complications

Complication Comments

Increased intracranial pressure Increased ICP usually develops 1–4 days after stroke but may occur acutely within hours. Manifestations include headache, decreased consciousness, papilledema, contralateral hemisphere signs, and upper brainstem compression. The diagnosis is made by CT or MRI, which shows brain edema and a shift in intracranial contents. Aggressiveness of treatment depends on the severity, location, and potential reversibility of the culprit brain lesion. Therapeutic measures include:

Head of bed elevation.• Modest fl uid restriction (2/3 of usual intake). Avoid • hypotonic solutions (D

5W, 0.5 NS), which may increase

cerebral edema.Intubation/hyperventilation to induce hypocapnia • (pCO

2 25–30 mmHg). Effects last 12–36 hr. Excessive

lowering of pCO2 may induce further ischemia. Opioids

and benzodiazepines help patients tolerate prolonged bed rest and hyperventilatory support. Ketamine, high positive end-expiratory pressure, volatile anesthetics, and tracheal suction can raise ICP.Control of pain and agitation.• Osmotic agents (mannitol, glycerol) to increase serum • osmolality to 300–310 mOsm. Mannitol is usually given as an initial dose of 0.5 gm/kg IV over 20 min, with repeat doses of 0.25 gm/kg q 4–6 hr as needed up to a maximum cumulative dose of 2 gm/kg/d. The effect on ICP usually occurs in ~20 min. Fluids lost during osmotic diuresis should be replaced intravenously to prevent a hyperosmolar state and dehydration. A rebound increase in ICP may occur upon withdrawal.Hypertonic saline may also be used, with the goal of • raising serum sodium to 145–155, and osms to the 300–320 range. IVs of 2–3% saline can be used for maintenance or to gently reduce ICP over hours; bolus doses of 30 mL of 23.4% saline can quickly reduce ICP in emergent situations. Hypotension is a complication.




Increased intracranial pressure High-dose barbiturates (e.g., thiopental 1–5 mg/kg) • rapidly lower ICP but may cause respiratory/myocardial depression and therefore require ventilatory support and BP monitoring.Drainage of CSF via intraventricular catheter for • secondary hydrocephalus.High-dose corticosteroids have not been shown to be • helpful in the setting of acute stroke. They are used for elevated ICP due to tumor or trauma. (Steroids may reduce extracellular vasogenic edema but are of little value for intracellular [cytotoxic] edema.)Surgical decompression via removal/drainage of • hematomas or infarcted temporal lobe/cerebellum. Hemicraniectomy can be performed to decompress ICP.

Seizures Seizures complicate 5–20% of strokes. Most can be managed with fosphenytoin (20 mg/kg phenytoin equivalents IV at a rate of up to 150 mg/min followed by phenytoin 100 mg PO q 8 hr to maintain blood levels of 10–20 mcg/mL). Benzodiazepines can be used to treat seizures acutely but increase the risk of respiratory depression and are not indicated for long-term control.

Deep venous thrombosis High incidence of DVT during recovery. Prevention is the key, with early ambulation, bedside physical therapy, and support hose or infl ated stockings. To prevent DVT, unfractionated heparin (5000 units SQ bid–tid) or low-molecular-weight heparin (enoxaparin, 30–40 mg/kg SQ q 12 hr or 1.5 mg/kg q 24 hr) should be administered in non-ambulatory patients in the absence of brain hemorrhage or other contraindications to anticoagulation.

Pulmonary embolism Treated with IV heparin unless recent brain hemorrhage. If multiple or life-threatening pulmonary emboli occur in the setting of recent brain hemorrhage, inferior venal caval umbrella or interruption is indicated. For large pulmonary embolisms with hemodynamic compromise and no brain hemorrhage, thrombolytic therapy can be considered.

Depression Depressive syndromes may be diffi cult to recognize in the stroke patient. Depression should be suspected if there is slower-than-expected recovery, poor cooperation in therapy, emotional lability, or fl attened affect. Patients may respond well to traditional pharmacologic therapy.

Table 5.1. Treatment of Stroke-Related Complications (cont’d)

Chapter 5. Stroke-Related Complications 47



Hypertension May be the cause or consequence of acute stroke. BP should not be treated in the acute stages of stroke unless >220/120 mmHg (or >185/110 mmHg after lytic therapy), as higher-than-normal BP may be needed to maintain perfusion to the brain. Exceptions include concomitant aortic dissection, acute MI, severe heart failure, or hypertensive encephalopathy. Aggressive lowering of BP increases the risk of further cerebral ischemia and neurologic deterioration, as autoregulation is impaired in the ischemic bed during the acute phase of stroke. BP usually declines spontaneously as pain, agitation, and increased ICP are controlled. When drug therapy is required, useful agents include sodium nitroprusside, labetalol, and calcium antagonists (sublingual nifedipine should be avoided). Guidelines for managing hypertension during thrombolytic therapy are described on p. 32.

Myocardial infarction MI occurs in up to 20% of patients with acute stroke and is a common cause of death between 1 and 4 weeks after stroke. High catecholamine levels, which accompany most strokes, may precipitate angina and MI. All patients should be carefully monitored for signs of myocardial ischemia/infarction. ECG changes following brain hemorrhage (especially SAH) can mimic acute myocardial ischemia/infarction, including ST-segment elevation or depression, giant upright or inverted T waves, prominent U waves, and prolonged QT interval. Cardiac markers (CK-MB, cardiac troponins) should be obtained in these cases to rule out acute MI.

Arrhythmias Sinus tachycardia, sinus bradycardia, and tachy-brady syndrome are not uncommon after stroke. Ventricular tachycardia has been reported, most often in association with a long QT interval (torsade de pointes). Cardioversion, antiarrhythmics, and pacemaker implantation are usually reserved for hemodynamic instability or symptoms.





Infections and sepsis Most episodes are caused by urinary tract infections (indwelling catheter, urinary retention) or pneumonia (aspiration, atelectasis). Preventive measures include intermittent bladder catheterization (preferred over continuous drainage), speech therapy with feeding guidance (feeding tube may be necessary), coughing and deep breathing exercises. A high index of suspicion for sepsis is essential, as fever, leukocytosis, and fl uctuating mental status often accompany stroke without infection. Prompt antimicrobial therapy is imperative.

Upper GI bleed Most episodes are caused by stress-related gastric mucosal damage (Cushing ulcers). Lesions can develop rapidly and may perforate or result in severe GI bleeding. Prevention is key: gastric pH >3.5 should be maintained with H

2 blockers,

proton-pump inhibitors, or sucralfate.

Hyponatremia Hyponatremia is an adverse prognostic factor following stroke and may be due to the SiADH. It is important to ensure euvolemia and exclude renal, adrenal, and thyroid disorders associated with hyponatremia.

Respiratory depression, depressed consciousness

More common in hemorrhagic strokes and large strokes complicated by increased ICP. Endotracheal intubation may be needed to protect the airway, along with ventilatory support, supplemental oxygen, and bronchopulmonary toilet.

Fever Fever is uncommon in the early hours of stroke and is associated with an adverse prognosis. Search for other causes (e.g., aspiration pneumonia, endocarditis) and treat. Administer antipyretic.

Malnutrition Give supplemental multivitamins and thiamine. Nasogastric tube supplements are recommended if intake is still poor by day 4. A gastric feeding tube may be required.

Contractures Preventive therapy with early physical therapy is essential.

Decubitus ulcers Meticulous attention to skin care is mandatory. Keep skin clean and dry, turn the patient frequently, and use padded boots and mattress. Wound debridement and skin grafting may be required in severe cases.


Chapter 5. Stroke-Related Complications 49


Chapter 6

Miscellaneous Topics in Cerebrovascular Disease


A. Asymptomatic Carotid Artery Stenosis 1. Stenosis >60%. The Asymptomatic Carotid Artery Stenosis Trial (ACAS; JAMA

1995;273:1421) evaluated the role of endarterectomy for healthy persons with >60% carotid artery stenosis by ultrasound. Event-free survival was improved by endarterectomy (stroke or death at 5 years: 11% with aspirin vs. 5.1% for surgery). However, surgeons were preselected, and overall surgical morbidity/mortality in the study were very low (<3%). Also, no benefi t was seen in women. The Asymptomatic Carotid Surgery Trial (ACST; Lancet 2004;363:1491) evaluated a similar population of patients, with essentially the same results—a 50% reduction in stroke risk for patients who underwent endarterectomy, so long as perioperative complications were minimized (<3%). This study did fi nd benefi t to carotid endarterectomy (CEA) for women. In summary, for well-selected patients, there is benefi t to CEA for stenosis >60%. However, based on both the ACAS and ACST, asymptomatic carotid stenosis is a low-risk condition, with a 2% per year event rate with medical therapy. Many of these events are TIAs, which are by defi nition nondisabling, and which would then move the patient into a symptomatic category, dramatically increasing the benefi t of endarterectomy. Patients and providers need to weigh the risk/benefi t carefully on a case-by-case basis prior to proceeding. CABG can be performed without carotid surgery if the patient is asymptomatic or symptoms are remote. For patients with recurrent TIAs or a prior nondisabling stroke, endarterectomy should be performed either prior to or simultaneously with CABG.

2. Stenosis < 60%. These patients should be managed with platelet inhibitors and control of risk factors for atherothrombosis (e.g., hypertension, dyslipidemia, diabetes, tobacco use, physical inactivity, obesity) (Chapters 9–14).

B. Unruptured Aneurysm. On average, rupture rates are 2–4% per year for asymptomatic aneurysms and 15% per year for symptomatic aneurysms. The risk of rupture increases with increasing size of aneurysm, and aneurysms in the posterior circulation are more likely to rupture than are aneurysms in the anterior circulation (Lancet 2003;362:103–110). Clipping, coiling, or ligation is indicated for aneurysms >5–7 mm in diameter and for aneurysms causing progressive neurologic symptoms secondary to compression. Operative mortality is low (<2%).

C. Carotid Endarterectomy . CEA is strongly indicated for severe symptomatic carotid artery stenosis (>70% narrowing) in men and women (see NASCET I, p. 156). It is also indicated for moderate symptomatic carotid artery stenosis (50–69%) in men (see NASCET II, p. 156), although the benefi t is not as large. CEA is indicated for asymptomatic carotid artery stenosis (>60%) if operative morbidity and mortality is less than 3%. There is no proven surgical benefi t for women with symptomatic carotid artery stenosis of 50–69%. For women with asymptomatic carotid artery stenosis >60%, the ACAS trial did not fi nd benefi t from surgery, but the ACST did; surgery can be considered in women so long



as comorbidities are low and it is understood by the patient that the benefi t may be marginal. Complications include death (1%), reocclusion (5–10%), and postoperative stroke (2–3%); complication rates are higher in patients with prior CEA and in diabetics. Postoperative MI occurs in 1% of patients without coronary artery disease, in 7% of patients with stable angina, and in 17% of patients with unstable angina.

D. Extracranial-Intracranial Bypass. Extracranial-Intracranial bypass is indicated for select patients with posterior circulation occlusive disease, acute intracranial occlusions, or chronic occlusive disease with persistent ischemia shown by PET or SPECT. Superfi cial temporal-to-middle cerebral artery shunts are not helpful if >6 weeks have elapsed since the ischemic insult.

E. Carotid and Vertebral Artery Stenting. Carotid stenting appears to be a feasible alternative to endarterectomy for carotid artery occlusive disease. Small studies indicate acceptable procedural success and complication rates, including restenosis rates of <10%. Results from the ARCHER and SAPPHIRE trials indicate that carotid stenting with distal embolic protection is a safe and effective alternative to CEA for patients at high surgical risk (Table 15.6, p. 157). If confi rmed in larger series, this procedure will be applicable to many patients with conditions that preclude standard operative therapy and may supplant operative therapy in some individuals. Angioplasty and stenting can also be performed successfully on stenotic vertebral arteries.

Chapter 6. Miscellaneous Topics in Cerebrovascular Disease 53


Chapter 7

Stroke Pitfalls


PITFALL: BASING TREATMENT OF STROKE ON BRAIN IMAGING ALONE WITHOUT A VASCULAR WORKUP

Defi nitive treatment of stroke should be based on the vascular workup, not the CT scan or MRI alone. For example, a left frontal stroke caused by a tight carotid stenosis should be treated with revascularization, while the same stroke caused by atrial fi brillation should be treated with warfarin.

PITFALL: BASING WORKUP AND TREATMENT ON TEMPORAL COURSE OF STROKE

Workup and treatment of stroke should focus on the vascular lesion, not the temporal course of neurologic symptoms. In fact, the vascular etiology of TIA, reversible ischemic neurologic defi cit, stroke in evolution, and completed stroke is often the same. In our practices, we fi nd that patients with TIA at community hospitals receive less workup (or no workup at all beyond a brain CT) than do patients with large strokes; patients with TIA have a 10% risk of stroke within 90 days (JAMA 2000;284:2901–2906). Furthermore, many patients with transient symptoms have small infarcts on imaging.

PITFALL: MISSING A MIMIC OF STROKE OR TIA

Transient neurologic defi cits can be caused by structural lesions (tumor, subdural hematoma, brain abscess), metabolic disturbances (especially hypoglycemia), partial seizures, meningitis/encephalitis, psychiatric syndromes, and migraine. Stroke mimics should be considered in all patients who present with an acute neurologic defi cit prior to institution of treatment.

PITFALL: MISSING EARLY INFARCT SIGNS ON CT

Sulcal effacement, loss of the “insular ribbon,” early hypodensity, and loss of gray-white differentiation (especially if large) increase the risk of hemorrhage during thrombolytic therapy. Careful assessment of the CT scan is necessary to ensure that thrombolytic therapy is given to only those patients in whom potential neurologic recovery outweighs the risk of ICH.



PITFALL: UNDERESTIMATING THE TIME OF SYMPTOM ONSET FOR PATIENTS WHO WAKE UP WITH A STROKE

Because most strokes are painless, patients may develop strokes in their sleep and wake up with a defi cit. In these cases, time of onset is unclear. Given the risks of late thrombolysis, onset time should be assumed to be the time when the patient was last observed to be well (i.e., when they went to sleep). These patients are almost always ineligible for thrombolytic therapy. In these cases, diffusion- and perfusion-weighted MRI and MRA may help to defi ne the benefi t/risk of thrombolytic therapy.

PITFALL: OVERTREATMENT OF HYPERTENSION IN ACUTE STROKE

Because acutely ischemic brain tissue is unable to autoregulate, overaggressive lowering of BP may lead to infarct extension and worse outcome. Hypertension should not be treated in the acute stages of stroke unless BP is >220/120 mmHg (or >185/110 mmHg if thrombolytics are used).

PITFALL: OVERUSE OF CAROTID ENDARTERECTOMY IN ASYMPTOMATIC PATIENTS

CEA is of proven value for symptomatic carotid disease. For patients who have > 60% carotid stenosis without symptoms, the benefi ts are much smaller (i.e., 1% annual reduction in sub-sequent risk of stroke). In asymptomatic patients, endarterectomy is indicated only if surgical risks are low (<3%). Endarterectomy for asymptomatic women was not shown to be benefi -cial in one study but was found to be benefi cial in another.

PITFALL: NOT INVESTIGATING BOTH EXTRACRANIAL AND INTRACRANIAL CIRCULATIONS

Embolic and thrombotic strokes can be caused by vascular lesions throughout the carotid and vertebrobasilar systems. Duplex imaging of the carotids, the most commonly ordered noninvasive test of the cerebral circulation, does not investigate the intracranial circulation. TCD, CTA, or MRA can noninvasively detect intracranial lesions, which are more common in Asians and Blacks.

Chapter 7. Stroke Pitfalls 57


PITFALL: FAILURE TO DISTINGUISH SEVERE CAROTID STENOSIS FROM TOTAL OCCLUSION

Neither carotid duplex imaging nor MRA can fully distinguish between severe stenosis (which is surgically amenable, possibly urgently) and total occlusion (where medical therapy is almost always indicated). Conventional angiography remains the test of choice.

PITFALL: INADEQUATE CARDIAC MONITORING/EVALUATION

Silent MI and arrhythmias are common stroke complications. MI occurs in up to 20% of patients with acute stroke and is a common cause of death at 1–4 weeks. All patients with acute stroke should undergo cardiac evaluation.

PITFALL: NOT OBTAINING SPINAL FLUID FOR PATIENTS WITH SUSPECTED SUBARACHNOID HEMORRHAGE

CT scan has 95% sensitivity for subarachnoid blood on the day of onset. Small hemorrhages can be missed, however, and CT sensitivity declines with increasing time from onset. If the CT is negative and the index of suspicion for SAH is high, LP is warranted.

PITFALL: NOT EDUCATING PATIENTS ABOUT SYMPTOMS OF STROKE

More than 90% of patients with acute ischemic stroke are ineligible for lytic therapy, in large measure due to late presentation from lack of awareness of common stroke symptoms. Furthermore, many patients with diabetes, hypertension, or dyslipidemia are unaware of the silent nature of these diseases and/or that they are at increased risk for stroke, contributing to noncompliance with medical therapy and progression of atherosclerosis. It is imperative to educate all individuals as to the warning signs of stroke, the need to seek immediate medical attention should symptoms develop, and the need to comply with primary and secondary prevention measures.



PITFALL: NOT CONSIDERING CAUSES OTHER THAN EMBOLISM IN PATIENTS WITH ATRIAL FIBRILLATION WHO DEVELOP ISCHEMIC STROKE

More than 25% of ischemic strokes in patients with AF are due to causes other than cardiogenic embolism, including intrinsic cerebrovascular disease and embolization of aortic arch atheroma. In such cases, additional measures may be required to prevent stroke recurrence (e.g., statins or carotid revascularization).

PITFALL: NOT TREATING PATIENTS WITH LARGE-ARTERY ISCHEMIC STROKE INDEFINITELY WITH ANTIPLATELET THERAPY

Long-term antiplatelet therapy reduces the risk of MI and stroke by 20% in patients with previous ischemic stroke due to large-artery atherothrombosis. Despite these convincing data, many eligible patients do not receive antiplatelet therapy. All patients with ischemic stroke due to large-artery atherothrombosis should be treated indefi nitely with either aspirin (81–325 mg once daily), clopidogrel (75 mg once daily), or combination low-dose aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily.

PITFALL: USING THE COMBINATION OF CLOPIDOGREL AND ASPIRIN IN PATIENTS WITHOUT A CARDIAC INDICATION

While the combination of clopidogrel and aspirin has been shown to be effective in preventing stent occlusion, recurrent MI, and death in patients with coronary artery disease, this combination was not found to be effective in a high-risk stroke population (MATCH study, see Chapters 11 and 15). The routine use of the combination of clopidogrel and aspirin for secondary stroke prevention should be avoided unless a specifi c cardiac indication for this regimen is in evidence.



PITFALL: FAILURE TO INSTITUTE MEASURES TO PREVENT EARLY STROKE-RELATED COMPLICATIONS

In addition to acute MI and arrhythmias, patients with stroke are at high-risk for serious medical complications caused by prolonged bed rest and immobility (decubitus ulcer, DVT, pulmonary embolism, depression, malnutrition) and as a direct consequence of the stroke itself (increased ICP, seizures, stress-induced GI ulcers, urinary voiding problems, aspiration pneumonia). It is important to routinely institute prophylactic measures to reduce these risks, including early ambulation, bedside physical therapy, support hose or infl ated stockings, subcutaneous heparin during prolonged immobilization (if not receiving IV heparin), intermittent bladder catheterization, coughing and deep-breathing exercises, maintenance of gastric pH >3.5 with H

2 blockers or other drugs, meticulous attention to skin care, nasogastric tube

supplements as required, and other measures as described on pp. 46–50.

PITFALL: FAILURE TO MAINTAIN BLOOD PRESSURE <180/105 mmHg DURING THROMBOLYTIC THERAPY

To minimize the risk of ICH during/after tPA, it is imperative to maintain SBP at <180 mmHg and DBP at <105 mmHg. IV labetalol is the antihypertensive drug of choice for this purpose (p. 32), but is not recommended in patients with signifi cant asthma, decompensated heart failure, or high-grade conduction disturbances. Nicardipine is an alternative, and nitroprusside may be used as well.

PITFALL: FAILURE TO RECOGNIZE LACUNAR STROKE

Lacunar stroke presents as one of several well-defi ned syndromes and is managed with long-term control of BP and possibly empiric antiplatelet therapy. Anticoagulation is not indicated. Lacunar syndromes include pure motor hemiparesis, pure sensory stroke, dysarthria- clumsy-hand syndrome, ataxic hemiparesis, and isolated motor/sensory stroke (pp. 24–25).

PITFALL: INADEQUATE USE AND DOSING OF HMG Co-A REDUCTASE INHIBITORS (STATINS) IN PATIENTS WITH CEREBROVASCULAR DISEASE

Statins reduce the risk of MI and stroke by 15–35% in patients with elevated LDL cholesterol levels. All patients with established cerebrovascular disease should have a lipid panel checked every 4–6 months, and a statin should be prescribed to bring LDL levels to 70–100 mg/dL (Chapter 13). Statins may also be useful in patients with arterial plaque/stenosis and “normal” cholesterol levels.



PITFALL: FAILURE TO LOWER CHRONIC HYPERTENSION TO ESTABLISHED TARGETS

Proper control of hypertension reduces the risk of death from stroke, coronary artery disease, and heart failure by 15–50%. Despite these benefi cial effects, only ~25% of patients with hypertension meet established guidelines. In one study, drug therapy was adjusted in only 7% of patients with BP >160/90 mmHg despite six or more hypertension-related visits per year (N Engl J Med 1998;339:1957). All patients should have their BP lowered to at least 140/90 mmHg; lower targets have been established for patients with diabetes or chronic renal disease (≤130/80 mmHg) (Chapter 12).

PITFALL: NOT DISCUSSING SMOKING CESSATION REGULARLY WITH PATIENTS

Continued cigarette smoking is a major risk factor for recurrent events in patients with cerebrovascular disease, yet less than one-third of patients discontinue smoking following a stroke. Regular and systematic discussion of the importance of smoking cessation can increase this discontinuation rate to almost 60%. Measures to assist patients willing to quit smoking and other therapeutic lifestyle changes (diet, physical activity, weight control) are described in Chapter 10.



Chapter 8

Controversies in Stroke Management


A. Stroke and Patent Foramen Ovale with/without Atrial Septal Aneurysm

Background Numerous studies have established an association between PFO and ASA in patients who have had a cryptogenic stroke. A meta-analysis of case-control studies comparing patients under age 55 who had ischemic stroke to control groups of non-stroke patients reported an increased likelihood of fi nding a PFO (OR, 3.1) or an ASA (OR, 6.1) in stroke patients (Neurology 2000;55:1172–1179).

Two prospective studies, one French (N Engl J Med 2001;345:1740–1746) and one American (PICSS, see p. 147), found no increased risk of recurrent stroke among patients with cryptogenic stroke and PFO, compared to patients with stroke of known cause. The recurrence rate ranged from 1.5% per year in the French study to 7.4% per year in the PICSS study, but in neither case did the recurrence rate differ from that seen in the control group. In neither study did the size of the PFO infl uence the recurrence rate.

Whether the presence of an ASD, in addition to a PFO, raises stroke risk, is also contro-versial. In the French study, the presence of an ASA tripled stroke risk compared to crypto-genic stroke patients without a PFO or ASA; in PICSS, the presence of an ASA did not increase recurrence.

Only the PICSS study prospectively and blindly followed patients with cryptogenic stroke and PFO on warfarin or aspirin. The annual stroke or death rate in the warfarin-treated group was 4.75% (versus 8.95% in aspirin-treated patients). This difference, about a doubling of the rate, did not reach statistical signifi cance because of very large confi dence intervals.

The Bottom Line Antiplatelet agents or anticoagulation with warfarin. The stroke risk in these patients is not high; nonetheless, they are at risk for developing red clot and having recurrent stroke. The PICSS study did not demonstrate benefi t for warfarin. Also, in PICSS, ASA did not confer additional risk. In comparing the two key studies, the biggest difference between the French study and the PICSS study is age: the average age in the French study was 42.5 years, and in PICSS, 58 years. This is the likely explanation for several of the fi ndings in PICSS; the big dif-ference in recurrence rate is likely due to the older population in PICSS. It is also possible that the negative fi nding with regard to ASA and increased stroke risk in PICSS is due to the age of the patients. It is possible that in an older population, such as the cohort in PICSS, many of the cryptogenic strokes were atherothrombotic and obscured an increased risk due to ASA found in other studies, resulting in a 5-fold increased recurrence rate in PICSS compared to the French study. The increased risk conferred by the PFO/ASA may have been obscured by strokes of other causes—the same phenomenon is seen in older patients with atrial fi brilla-tion, where 25–30% of strokes are not caused by the atrial fi brillation. Nonetheless, the only prospective data on warfarin versus aspirin is provided in the PICSS study, which showed a trend toward benefi t for warfarin, which was not statistically signifi cant. In a younger popu-lation, where strokes of other causes are much less likely, a treatment difference might have been seen. Some clinicians aggressively look for venous clots in these patients and, even if



they do not fi nd them, strongly consider warfarin in younger patients and in patients with PFO and ASA. They explain to patients that PFO is a low-risk condition and that there is a trend—but no certainty—toward benefi t from warfarin. In older patients (who closely match the cohort in PICSS), some clinicians still look for clot but are much more comfortable with prescribing aspirin.

PFO closure. Closure has been available for a number of years, and several trials are under-way (comparing closure to “best medical therapy”), but no data prove its effectiveness. Given that PFO places the patient at low recurrence risk, the complication rate would have to be exceedingly low to make a compelling case. In my opinion, PFO closure for cryptogenic stroke should not be undertaken outside a clinical trial.

An American Academy of Neurology Practice Parameter is available on this topic (Neurology 2004;62:1042–1050).

B. Large Hemispheric Stroke within 3–6 Hours

Options 1. IV tPA. IV tPA has recently been shown (in ECASS III, see p. 153) to be effective

in a 3–4.5-hour window in carefully selected patients. However, patients in this trial had relatively mild strokes, and exclusion criteria were rather strict. The absolute benefi t of treatment was 7%, much lower than the 11–12% seen in the NINDS tPA trial or the 15% seen in PROACT II (see p. 155). The placebo group in the ECASS III study had comparable functional outcomes to the tPA-treated group in the NINDS trial–45% of patients in the placebo group had a good outcome; this attests both to the relative mildness of the strokes, as well as to the quality of care in modern stroke units. Last, tPA is not approved for use in stroke beyond 3 hours.

2. IA tPA. In the PROACT II study, IA prourokinase was shown to improve outcomes in patients with MCA stroke treated within 6 hours. The absolute difference between IA prourokinase and placebo-treated patients was 15%. This was one of the most scientifi cally sound studies done in stroke, as the vascular lesion treated—proximal MCA occlusion—was similar in all patients, and the natural history is a poor outcome without treatment. This methodology allowed for a small trial (only 180 patients) to yield a statistically and clinically meaningful result. However, because prourokinase is not commercially available, tPA is used for IA therapy. While it is technically “off label” and not FDA approved for this indication, it has nonetheless been used intra-arterially in acute stroke for >10 years. Numerous case series document reasonable effi cacy and safety.

3. MERCI. The MERCI retriever has been approved by the FDA for use in this setting within 8 hours of symptom onset. However, because of differences in the approval process for devices and medications, this device was approved on the basis of a nonrandomized trial that used historical controls. Technically, the approval is not for acute stroke per se , but to recanalize a large-vessel occlusion in the setting of acute

Chapter 8. Controversies in Stroke Management 65


stroke (a plumbing problem). In the MERCI trial, only 28% of patients had a good outcome at 90 days (defi ned as an MRS of £2); this does not compare well with the PROACT II (prourokinase) trial, where 40% of patients achieved the same outcome, or even the placebo group in PROACT II, which had a comparable outcome (25% of patients with MRS £2). MR RESCUE, an RCT (with MRI to help defi ne who is most likely to benefi t) comparing MERCI retriever with IV tPA as a control, is underway. In support of the use of the MERCI device are the following points:

a. Treatment in the MERCI trial was within 8 hours, versus 6 hours in PROACT II; therefore, the clinical outcomes are not directly comparable. Furthermore, the patients in MERCI had more severe neurologic defi cits (NIH stroke scale was median 20 in MERCI, 19 in Multi MERCI, compared to 17 in PROACT II).

b. While not an RCT, the MERCI trial did have a “built in” control group—patients who did not recanalize did poorly, with a <10% recovery rate, whereas patients who did recanalize had good outcomes approximately 50% of the time.

c. In Multi MERCI (see p. 158), recanalization approached 70% when multiple modalities were permitted. Clinical outcome was better in Multi MERCI when compared to MERCI, at 36%, approaching the outcome in PROACT II, which approached 40% in the prourokinase-treated group.

The Bottom Line IV tPA is the least likely to be benefi cial of the three options, although it is also the most widely available and easiest to administer. The two IA treatments offer the advantage of angiography to better defi ne vascular pathology. Between IA tPA and the MERCI retriever, this is an “either and” as opposed to an “either or” situation. Both techniques have clinical usefulness in patients with proximal clot and acute stroke. Depending on vessel anatomy and the experience of the angiographer, one technique may be chosen, followed by the other. I have personally seen many situations in which the fi rst modality—IA tPA or MERCI—has worked well, cases in which neither has worked, and cases in which the second technique chosen has worked with excellent clinical outcomes.

C. Hemicraniectomy for Malignant MCA Stroke

Background Malignant MCA infarcts are large MCA strokes in which edema leads to progressively increased ICP, decreased neurologic function, and often herniation and death. The fatality rate with conservative therapy is 80% (Curr Opin Crit Care 2007;13:175–179). Multiple therapeutic strategies, including osmotic therapy, hyperventilation, barbiturates, steroids, and hypothermia, have been tried; some have proven detrimental (steroids), some are short-term temporizing measures (hyperventilation, osmotic therapy), and others continue to be investigated (hypothermia). Decompression offers the chance to dramatically reduce ICP, allow-ing the brain to swell out—not across or down. Because ICP drops, perfusion to the ischemic



penumbra increases, resulting, theoretically, in smaller fi nal infarct size and better functional outcomes. Three prospective randomized clinical trials—DECIMAL (Stroke 2007;38:2506–2517), DESTINY (Stroke 2007;38:2518–2525), and HAMLET (Lancet Neurology 2009;8:303–304)—have evaluated hemicraniectomy compared to conservative therapy in this syndrome. A meta-analysis of the three trials (Lancet Neurology 2007;6(3):215–222), with 93 patients, reported a dramatic survival benefi t to decompression (78% for patients undergoing hemicraniectomy versus 29% with conservative treatment). Equally importantly, a larger proportion of patients in the decompressive surgery group than in the control group achieved moderate disability or better, as defi ned by an MRS score of £3 (43% versus 21%).

Pro: Improved survival, including some patients with mild-to-moderate disability.Con: Many patients will not do well and, if they survive, will live a life of misery and hopelessness.

The Bottom Line The surgery is effective and lifesaving for patients with malignant MCA infarcts on either side. On a per-case basis, the benefi ts are larger than for many other therapies, including some therapies that have no scientifi c proof of effi cacy. For hemicraniectomy, only four patients need be treated to have one additional patient survive with an MRS score of £3.For every 10 hemicraniectomies performed for MCA infarction, fi ve additional patients sur-vive; at 1 year, one of these patients will have mild disability, one will have moderate dis-ability, and three will have moderate-to-severe disability (Stroke 2007;38:2410–2412). These studies do have limitations: all enrolled patients were £60 years of age, and surgeries were performed within 48 hours; therefore, there are questions about older populations. The key to addressing this issue appropriately is understanding the data and being able to convey it in an understandable manner to family members during the consent process.

D. Craniotomy/Evacuation for Supratentorial ICH

Options 1. Surgery.

a. Rapid surgical evacuation of other space-occupying lesions, including subdural hematomas within 4 hours, dramatically improves clinical outcomes (N Engl J Med 1981;304:1511–1518).

b. The mechanism of injury in ICH includes increased pressure locally and throughout the intracranial space, resulting in decreased perfusion and an ischemic penumbra. Surgical evacuation rapidly reduces intracerebral pressure.

c. A meta-analysis of 12 surgical trials (including STICH, see p. 171) has shown a reduction in mortality associated with surgical treatment. The benefi t seemed greater for lobar hemorrhage (Curr Opin Crit Care 2007;13:169–174). Anecdotally, we have all seen patients in whom surgery has been lifesaving, sometimes with reasonable recovery of function in cerebellar hemorrhage, where evacuation of



the clot is routinely done and considered standard of care. Lastly, while the STICH trial was large, it was methodologically fl awed: the time to surgery was too long (the average time from the onset of symptoms to surgery was 30 hours; in only 16% was surgery done within 12 hours), and patients with superfi cial and deep hemorrhages, with or without intraventricular blood or hydrocephalus, were mixed together. A new British-based trial, STICH II, comparing conservative management with surgical evacuation for hematomas £1 cm below the cortical surface, is enrolling patients.

2. Medical treatment.

a. Multiple surgical trials have failed to fi nd a benefi t to surgery, including STICH. The damage done by blood and increased pressure has already occurred before the patient can be taken to the operating room.

b. The surgical track that is necessary to evacuate blood from deep-seated structures (e.g., the basal ganglia or thalamus) will result in a major contralateral defi cit. The combination of blood, surrounding ischemia, and surgical evacuation results in a poor outcome.

c. These patients often have a coagulopathy that makes bleeding likely.

The Bottom Line These patients need to be considered on a case-by-case basis. Superfi cial hematomas with signifi cant neurologic defi cits should be evacuated. For deep-seated hematomas, patients with recent deterioration should be considered for surgical evacuation. Patients with hydrocephalus should at minimum have an inferior vena cava fi lter placed. A trial of hyperventilation and osmotic or hypernatremic therapy can also be considered, with patients who improve then considered for surgery.

E. Antiplatelet Agents to be Used for Secondary Stroke Prevention, especially “Aspirin Failure”

Options 1. Aspirin . Aspirin is cheap, generally well tolerated, and widely available. In studies

including more than 23,000 patients it reduces recurrent stroke risk by 13%. In higher-risk patients, the benefi t is approximately 25%. Studies have shown that high-dose and low-dose aspirin work equally well, and two randomized studies comparing different dosages have found no benefi t to higher doses, with doses ranging from 30 mg/d to 1200 mg/d equally effi cacious (N Engl J Med 1991;325:1261–1266; J Neurol Neurosurg Psychiatry 1991;54:1044–1054). The FDA’s offi cial recommendation for aspirin in stroke prevention is 50–325 mg/d.



2. Clopidogrel or the combination of aspirin and extended-release dipyridamole . Clopidogrel is well tolerated, is given once per day, and has ample data in cardiovascular disease proving effi cacy. In terms of stroke, the data are less clear cut, as the CAPRIE study did not show a statistically signifi cant benefi t in patients who enrolled in the study for stroke (the FDA approval is for prevention of atherothrombotic events in patients with stroke). However, even in CAPRIE, the nonsignifi cant benefi t was 7.3% in favor of clopidogrel over aspirin. And the recent PRoFESS trial (see p. 147) showed that clopidogrel performed comparably with aspirin and extended-release dipyridamole.

However, the ESPS 2 study showed that combination aspirin and extended- release dipyridamole worked 23% better than did low-dose aspirin, a statistically and clinically signifi cant result that is far larger than the benefi t of clopidogrel over asprin in CAPRIE (8.7% risk reduction compared to 325 mg of aspirin). Despite this, in PRo-FESS, clopidogrel and combination aspirin/dipyradmole performed comparably in a direct, head-to-head trial. However, the event rate in PRoFESS was lower than had been expected when the trial was initially proposed, and it is therefore possible that the virtual tie between clopidogrel and the combination of aspirin and dipyridamole represents an antiplatelet agent “ceiling effect”—in a clinical trial, with extra resources designed to maximize compliance and efforts to treat all comorbidities, there was not a big difference between these two treatments, but this is not a typical situation. Lastly, had the PRoFESS study included an aspirin arm, we would have a much better understanding of the benefi t of these two therapies relative to aspirin, and of the results of the trial.

The Bottom Line In a sense, this is a trick question. While both clopidogrel and the combination of aspirin and extended-release dipyridamole work at least as well as aspirin, and probably, on the basis of CAPRIE and ESPS-2, a little better, I would focus my attention on alternate treatment options. When patients have a recurrent stroke on aspirin, I closely evaluate the patient’s previous and current workup to ensure I am not missing other treatable causes, mainly cardiac, aortic arch, and carotid, as well as intracranial disease. I then focus on treating the whole patient, not just on picking an antiplatelet agent. Ensure that BP is optimized (130/80 or less), glucose control is adequate, all components of cholesterol are optimal, and that the patient is actively managing his or her lifestyle, including diet and exercise. Does the patient have other potential comorbidities that predispose to stroke, such as sleep apnea? These efforts are much more likely to be benefi cial to the patient than switching an antiplatelet agent would be.

After doing all of the above, my tendency is to offer these patients the option of switching to either clopidogrel or aspirin and dipyridamole. If patients have active cardiac disease, I switch to clopidogrel. I do not use the combination of aspirin and clopidogrel unless there is a clear indication for it.



F. Timing of Carotid Surgery after Recent Stroke

Options 1. Early. Symptomatic patients who have >50% carotid stenosis are at high risk for

recurrent stroke. Rothwell and colleagues pooled data from two large CEA trials (ECST and NASCET, see p. 156). They found that the benefi t from surgery was greatest in men, in patients 75 years or older, and those randomized within 2 weeks after their last ischemic event. The benefi t fell rapidly with increasing delay. For patients whose surgery was within 2 weeks after their last ischemic event, one stroke was prevented for every fi ve patients who underwent surgery. If surgery occurred more than 12 weeks after the last ischemic events, one stroke was prevented for every 125 surgeries (Lancet 2004;363:915–924).

2. Late . Surgeons are reluctant to operate early because of an increased risk of hyperperfusion injury and ICH. The risk is greatest in patients with large strokes, high-grade stenosis, and uncontrolled BP.

The Bottom Line Early surgery—within days—is appropriate for patients with TIA as the symptomatic event and for patients with small nondisabling strokes. These patients remain at high risk until the vascular lesion is addressed. For patients with comorbidities that increase the risk of surgery, these can be addressed quickly within a week or two. Urgent, aggressive BP control is warranted for patients with uncontrolled hypertension, and surgery can proceed once BP is controlled. Postoperative management focusing on continued aggressive BP monitoring and control is crucial to a good outcome. For patients with large strokes, it is not unreasonable to defer surgery for 4–6 weeks.

G. Acute Mild Stroke: To Treat or Not to Treat

Background Patients who come into the hospital immediately after onset of stroke symptoms are often not treated with thrombolysis because their symptoms are too mild. In one study, which evaluated 128 consecutive patients who arrived at the Massachusetts General Hospital (MGH) within the tPA time window, 41 of 128 patients were not treated because their symptoms were too mild (Stroke 2005;36:2497–2499). This was the most common reason for not treating. While the NINDS tPA trial is often given as a reason not to treat patients with mild symptoms, the only inclusion criterion referring to severity in that trial was “a defi cit measurable on the NIHSS” (N Engl J Med 1995;333:1581–1587).

An analogous situation is whether to treat patients whose symptoms are getting better. “Symptoms improving” is another commonly used exclusion criterion. The NINDS paper cites as an exclusion “rapidly improving or minor symptoms.”

The main issue here is understanding relative and absolute exclusion criteria and properly weighing risks and benefi ts: balancing the risk of a bad neurologic outcome related to the stroke versus the risk of a hemorrhagic complication.



Options 1. Treat. Multiple lines of reasoning apply here, as follows:

a. Not all symptoms should be viewed by the treating physician in a similar fashion. Resist the tendency to treat an NIHSS score and not the patient. The key question is, “Is this patient having a disabling stroke?” Language defi cits, motor function, side of the defi cit (dominant versus nondominant), gait, and patient-specifi c issues (such as work, social support, and hobbies) may all infl uence the treatment decision. Without treatment, a patient with a densely paretic leg but no other defi cits from an ACA infarct is unlikely to be able to return to ambulation but would only get 2 points on an NIH stroke scale, whereas a demented patient with a thalamocapsular lacune may get 6–8 points on an NIHSS but be able to return to his/her prior level of functioning. I would advocate applying both a longer view and a more functional approach: How is this patient likely to look in 3 months or more (assuming no worsening)? Are these defi cits likely to be disabling? If the patient is likely to do well with rehabilitation, and not be disabled, it is often reasonable not to treat. In the MGH paper cited above, 5 of the 41 patients who were “too good to treat” were unable to be discharged home because of “mild but persistent symptoms.”

b. Think about the vascular lesion as opposed to the magnitude of defi cits. This applies to all patients but is particularly important in patients with mild or waxing/waning symptoms, as well as in patients who are rapidly improving. Often, patients will present with symptoms suggestive of a top-of-carotid or MCA-stem occlusion (lethargy, gaze preference, neglect or aphasia, and hemiplegia) but then clear to an inferior division MCA syndrome. Technically, these patients have rapidly improved and are often not treated. Because of the paucity of motor symptoms, these patients may do well on an NIH stroke scale, but they may have a tight proximal lesion. Because of the presence of subtle cortical signs not covered in an NIH stroke scale, these patients may have severe neurologic impairments, especially cognitive. In the MGH paper, 10 patients were not treated because of rapid symptom improvement. Of these 10 (which constitute 25% of the “too good to treat” population), 6 were unable to be discharged home because of subsequent worsening. Two of these patients died—both had right ICA stenosis with embolism to the right MCA; each initially had rapid improvement but subsequently worsened with the development of large MCA territory infarctions.

c. The risks of tPA are greater with increased stroke severity, as well as with age and (probably) time to treatment. Uncontrolled hypertension also increases risk. In these cases, given that the stroke is relatively mild, the risk of bleeding is low. In the ECASS III trial, with a 4.5-hour time window, the risk of ICH was only 2.4%.

2. Don’t Treat. The patient’s symptoms are mild, and the risk of bleeding, while small, is not insubstantial. In mild cases, there is often the concern that the fi nal diagnosis will not be stroke or TIA, but a migraine or partial seizure. Protocols drive practice because they ensure consistent practice over time.



The Bottom Line Each of these patients should be considered as an individual, and treatment should be strongly considered in all patients who have an acute ischemic stroke with a persistent defi cit. Patients with cortical strokes tend to have permanent disabilities more often than do patients with subcortical strokes; the presence of cortical signs should be considered in the treat/don’t treat decision. In addition, careful consideration of the likely mechanism of the initial symptoms and the potential mechanisms for the observed improvement, embolus migration, hemodynamics, and collateral fl ow, is helpful. Lastly, vascular imaging (by CTA, TCD, or angiography), if it can be done expeditiously, may tilt the balance one way or the other. The presence of clot in the appropriate vessel would strongly imply that the patient is likely to get worse; the absence of any visible clot could mean that this is a nonvascular syndrome, that the patient’s symptoms will get fully better, or that this is a small or distal occlusion, all of which have a reasonably good prognosis.



SECTION 2

CEREBROVASCULAR AND CARDIOVASCULAR RISK REDUCTION

Chapter 9. Overview of Cerebrovascular and Cardiovascular Risk Reduction. . . . . . 75 Chapter 10. Therapeutic Lifestyle Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Chapter 11. Antiplatelet and Antithrombotic Therapy for the

Prevention of Recurrent Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . .101 Chapter 12. Control of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113 Chapter 13. Control of Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123 Chapter 14. Other Measures to Prevent Atherothrombosis and Stroke . . . . . . . . . .133


Chapter 9

Overview of Cerebrovascular and Cardiovascular Risk Reduction


Atherothrombotic vascular disease is the leading cause of morbidity and mortality in developed countries, accounting for more than one-third of all deaths each year. At any one time, 12 million Americans have coronary heart disease (CHD), 4.7 million have had strokes, and millions more have claudication from peripheral arterial disease. Of the 800,000 Americans who have a stroke each year, 5–15% will have a recurrence by 1 year. By 5 years, up to 40% will have had a recurrent stroke and almost 50% will have died, usually from cardiovascular disease (Table 9.1). Hypertension is a major modifi able risk factor for atherosclerosis and frequently coexists with other important risk factors, including dyslipidemia, diabetes mellitus, tobacco use, obesity, and sedentary lifestyle (Table 9.2). Lifestyle modifi cations, pharmacologic measures, and surgical therapy can reduce the risk of stroke by 20–50%. Therapeutic lifestyle changes are recommended for all patients, while use of antiplatelet agents, anticoagulants, and arterial revascularization (endarterectomy or stents) requires individualization. Chapters 10–14 detail proven risk reduction measures aimed at halting the progression of atherosclerosis, stabilizing rupture-prone plaques, preventing arterial thromboembolism, and improving prognosis.

Table 9.1. Annual Risk of Stroke or Vascular Death for Individuals with Cerebrovascular Disease

Annual Risk (%)

Characteristic Stroke Vascular Death

General elderly male population 0.6 –

Asymptomatic carotid stenosis 1.3 3.4

Transient monocular blindness 2.2 3.5

Transient ischemic attack 3.7 2.3

Minor stroke 6.1 3.2

Major stroke 9.0 3.5

Symptomatic carotid stenosis >70% 15.0 2.0

From: Arch Neurol 1992;49:857.



Table 9.2. Modifi able Risk Factors for Ischemic Stroke

Factor Prevalence (%) Relative Risk of Stroke

Hypertension 25–40 3–5

Elevated total cholesterol (>240 mg/dL)

25–40 1.8–2.6

Smoking 25 1.5

Physical inactivity 25 2.7

Obesity 18 1.8–2.4

Asymptomatic carotid stenosis >50%

2–8 2

Alcohol >5 drinks/d 2–5 1.6

Atrial fi brillation 1 5 (nonvalvular)17 (valvular)

From: JAMA 2002;288:1388–1395.

Chapter 9. Overview of Cerebrovascular and Cardiovascular Risk Reduction 77


Chapter 10

Therapeutic Lifestyle Changes


Diet modifi cation, weight control, and increased physical activity are important therapeutic lifestyle changes for all patients at risk of atherothrombosis. For patients who require drug therapy for hypertension or dyslipidemia, the drug should be added to, not substituted for, diet modifi cation and other lifestyle changes.

DIET MODIFICATION

A diet high in citrus fruits and cruciferous and green leafy vegetables was shown to protect against ischemic stroke in the Framingham study (JAMA 1995;273:1113) and the Nurses Health Study (JAMA 1999;282:1233); each increment of one daily serving reduced the risk of ischemic stroke by 6%. Long-term data from the Nurses Health Study (AIM 2008;168(7):713) showed that adherence to this Dietary Approaches to Stop Hypertension (DASH) diet—high in fruits and vegetables, moderate in low-fat dairy products, and low in animal protein but with substantial amount of plant protein from legumes and nuts—reduces the risk of both CHD and stroke over 24 years of follow-up. JNC VII (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) recommends the DASH diet as part of a comprehensive program to reduce vascular risk.

A Cochrane review of multiple randomized trials that compared dietary advice for reducing cardiovascular risk with no advice, found multiple benefi ts: signifi cant reductions in total serum cholesterol, LDL, and systolic and diastolic BPs. The authors conclude a possible reduction in stroke risk by over 10% due to the magnitude of BP reduction ( Cochrane Database of Systematic Reviews 2007, Issue 4).

A diet low in saturated and trans fats and possibly high in omega-3 fats is also recommended. Light-to-moderate alcohol consumption (1 drink/week to 2 drinks/d) may reduce the risk of ischemic stroke in men by 20% over 12 years (N Engl J Med 1999;341:1557; Stroke 2006;37:13–19), but heavy alcohol consumption (>5 drinks/d) increases the risk of stroke. By limiting total fat, saturated fat, and dietary cholesterol in patients consuming a typical Western diet, initiation of the Therapeutic Lifestyle Changes (TLC) diet (Tables 10.1, 10.2), advocated by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (Circulation 2002;106:3143–3421), can lower LDL cholesterol levels by 10–20%. A registered dietitian can be helpful in improving compliance. Other dietary measures to lower LDL cholesterol and reduce risk of atherothrombotic vascular disease are described in Table 10.3.

Fluid intake is also important. Many older individuals take in an inadequate fl uid volume, especially in the evening, in order to decrease night-time urination. Intake of at least six to eight 8-ounce glasses of fl uid per day should be encouraged.



Table 10.1. Therapeutic Lifestyle Changes (TLC) Diet

Food Composition Recommendation

Total fat 25–35% of total calories Saturated fat* <7% of total calories Polyunsaturated fat Up to 10% of total calories Monounsaturated fat Up to 20% of total caloriesCarbohydrates 50–60% of total calories†

Fiber 20–30 gm/dProtein ~15% of total caloriesCholesterol <200 mg/dTotal calories Suffi cient to achieve/maintain desirable body weight

* Trans fats also raise LDL cholesterol and should be kept to a minimum.† More than half as complex carbohydrates from whole grains, fruits, vegetables.

Table 10.2. Components of the TLC Diet: Recommendations from NCEP-ATP III

Component Evidence Statement* Recommendations

Total fat Unsaturated fats do not raise LDL cholesterol when substituted for carbohydrates in the diet (A2, B2).

It is not necessary to restrict total fat intake for the purpose of reducing LDL cholesterol, provided saturated fats are reduced to goal levels.

Saturated fats High intakes of saturated fats raise LDL cholesterol and are associated with high population rates of CHD (C2). Reduction in intake of saturated fats reduces CHD risk (A1, B1).

A therapeutic diet to maximize lowering of LDL should contain <7% of total calories as saturated fats.

Trans fats Trans fats raise LDL cholesterol (A2). Prospective studies support an association between higher intakes of trans fatty acids and CHD incidence (C2).

Intakes of trans fats should be kept low. Liquid vegetable oil, soft margarine, and trans fat–free margarine are encouraged instead of butter, stick margarine, and shortening.

Polyunsaturated fats Linoleic acid, a polyunsaturated fat, reduces LDL cholesterol levels when substituted for saturated fats (A1, B1). Clinical trials indicate that substitution of polyunsaturated fats for saturated fats reduces risk for CHD (A2, B2).

Polyunsaturated fats can replace saturated fat. Most polyunsaturated fats should be derived from liquid vegetable oils, semi-liquid margarines, and margarines low in trans fats. Intake can range up to 10% of total calories.

Chapter 10. Therapeutic Lifestyle Changes 81


Component Evidence Statement* Recommendations

Monounsaturated fats

Monounsaturated fats lower LDL cholesterol relative to saturated fatty acids (A2, B2) but do not lower HDL cholesterol or raise triglycerides (A2, B2). Diets rich in monounsaturated fats provided by plant sources; and rich in fruits, vegetables, and whole grains; and low in saturated fats decrease CHD risk (C1).

Monounsaturated fats are one form of unsaturated fatty acids that can replace saturated fats. Intake can range up to 20% of total calories. Most monounsaturated fats should be derived from vegetable sources, including plant oils and nuts.

Cholesterol High intakes raise LDL cholesterol (A2, B1) and the risk for CHD. Reducing intakes from high to low decreases LDL cholesterol (A2, B1).

Less than 200 mg/d of cholesterol should be consumed in the TLC Diet to maximize lowering of LDL cholesterol.

Carbohydrates When carbohydrate is substituted for saturated fats, LDL cholesterol levels fall (A2, B2). However, very high intakes of carbohydrate (>60% of total calories) are accompanied by a reduction in HDL cholesterol and a rise in triglyceride (B1, C1).

Daily intake should be limited to 60% of total calories in persons with a metabolic syndrome. Lower intakes (e.g., 50% of calories) should be considered for persons who have elevated triglycerides or low HDL cholesterol. Most carbohydrates should come from grain products (especially whole grains), vegetables, fruits, fat-free/low-fat dairy.

Protein Dietary protein in general has little effect on LDL cholesterol or other lipoprotein fractions. However, substituting soy protein for animal protein has been reported to lower LDL cholesterol.

Protein intake should constitute ~15% of total calories. Plant sources include legumes, dry beans, nuts, and to a lesser extent, grain products and vegetables, which are low in saturated fats/cholesterol. Animal sources of protein that are lower in saturated fat/cholesterol include fat-free/low-fat dairy, egg whites, fi sh, skinless poultry, lean meats.

* Type of Evidence: A: Major RCTs; B: Smaller RCTs and meta-analyses of other clinical trials; C: Observational and metabolic studies; D: Clinical experience.

Strength of Evidence: 1: Very strong; 2: Moderately strong; 3: Strong trend.

Adapted from: National Cholesterol Education Program Adult Treatment Panel III Report. Circulation 2002;106:3143–3421.

Table 10.2. Components of the TLC Diet: Recommendations from NCEP-ATP III (cont’d)



Table 10.3. Dietary Options for LDL Lowering and Cardiovascular Risk Reduction: Recommendations from NCEP-ATP III

Measure Evidence Statement* Comments

Increasing viscous fi ber in the diet

5–10 gm/d of viscous fi ber reduces LDL cholesterol levels by ~5% (A2, B1).

The use of dietary sources of viscous fi ber is a therapeutic option to enhance LDL lowering.

Plant stanols/sterols Intakes of 2–3 gm/d of plant stanol/sterol esters reduce LDL cholesterol by 6–15% (A2, B1).

Plant stanol/sterol esters are a therapeutic option to enhance LDL lowering.

Soy protein High intakes of soy protein can cause small reductions in LDL cholesterol levels, especially when it replaces animal food products (A2, B2).

Food sources containing soy protein are acceptable as replacements for animal food products containing animal fats.

n-3 (omega-3) polyunsaturated fatty acids

Higher intakes of n-3 fatty acids may reduce risk for coronary events/mortality (A2, C2).

Higher dietary intake of n-3 fatty acids in the form of fatty fi sh or vegetable oils is an option for reducing CHD risk.

Folic acid and vitamins B6

and BI2

Elevated homocysteine levels are an independent risk factor for stroke, but the VISP study failed to fi nd a signifi cant benefi t to vitamin supplementation. A larger study, VITATOPS, has yet to report. See Chapter 14.

ATP III endorses the Institute of Medicine RDA for dietary folate (400 mcg/d).

Antioxidants Clinical trials have failed to show that antioxidant supplements reduce CHD risk (A2).

The Institute of Medicine’s RDAs for dietary antioxidants are recommended (vitamin C, 75 mg and 90 mg/d for women and men; vitamin E, 15 mg/d).

Moderate alcohol intake Moderate alcohol intake in middle-aged/older adults may reduce CHD risk (C2). High intakes of alcohol produce multiple adverse effects (C1).

Alcohol should be limited to 2 drinks/d for men and 1 drinks/d for women. A drink is defi ned as 5 oz. wine, 12 oz. beer, or 1.5 oz. 80-proof whiskey.



Measure Evidence Statement* Comments

Dietary sodium, potassium, and calcium

Lower salt intake lowers blood pressure or prevents its rise.

ATP III and JNC VII recommend a sodium intake <2.4 gm/d sodium or 6.4 gm/d sodium chloride and adequate intakes of dietary potassium (~90 mmol/d), calcium, and magnesium.

Herbal or botanical dietary supplements

Trial data are not available to support the use of herbal and botanical supplements in the prevention or treatment of heart disease.

ATP III does not recommend use of herbal or botanical dietary supplements to reduce CHD risk. Because of potential drug interactions, patients should be asked whether such products are being used.

Weight loss regiments that are high in protein, total fat, and saturated fat

These diets have not been shown in controlled trials to produce long-term weight reduction, and their nutrient composition does not appear to be conducive to long-term health.

These regimens are not recommended for weight reduction in clinical practice.

* Type of Evidence: A: Major RCTs; B: Smaller RCTs and meta-analyses of other clinical trials; C: Observational and metabolic studies; D: Clinical experience.

Strength of Evidence: 1: Very strong; 2: Moderately strong; 3: Strong trend.

Adapted from: National Cholesterol Education Program Adult Treatment Panel III Report. Circulation 2002;106:3143–3421.

MEDITERRANEAN-STYLE DIET

A. Mediterranean Diets. Increasing evidence suggests that a Mediterranean-style diet that emphasizes consumption of monounsaturated and omega-3 fatty acids can play an important role in the prevention of atherothrombotic vascular disease. The Lyon Heart Study randomized 605 post-MI patients to a Mediterranean diet that provided increased

Table 10.3. Dietary Options for LDL Lowering and Cardiovascular Risk Reduction: Recommendations from NCEP-ATP III (cont’d)



levels of alpha-linolenic acid (from olive oil and canola oil) or to usual dietary instruction. Patients in the Mediterranean-diet group were instructed to consume more fi sh, bread, and root and green vegetables; eat less meat; have fruit at least once daily; and use canola-based margarine and olive oil as a fat source. After 27 months, patients on the Mediterranean diet showed a 70% reduction in all-cause mortality (p = 0.03). The rate of cardiovascular death and nonfatal MI was 1.32 per 100 patient years in the treated group compared to 5.55 per 100 patient years in the control group (p = 0.001) (Lancet 1994;343:1454–1459). Benefi ts were maintained at 4 years (Circulation 1999;99:779–785). In an Indian study including 1000 patients post-MI, an Indian version of the Mediterranean diet reduced MI and stroke by 50% over 2 years—this despite the fact that 60% of the study’s participants were already vegetarian (Lancet 2002;360:1455–1461).

B. Other Studies. Further evidence for the vascular protective effects of omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) from fi sh or fi sh oil supplements comes from the GISSI Prevention study and Diet and Reinfarction Trial (DART). The GISSI Prevention study randomized 11,324 Italian men and women (who presumably were eating a Mediterranean diet) with MI within the preceding 3 months to omega-3 fatty acids (850–882 mg/d), vitamin E (300 mg/d), both, or neither. After 3.5 years, the omega-3 group had a signifi cant 20% reduction in all-cause mortality and 45% reduction in sudden cardiac death (Lancet 1999;354:447–455). In DART, 2033 men with prior MI were randomized to receive different types of dietary advice to prevent another MI. After 2 years, the group told to increase their omega-3 intake by eating oily fi sh (e.g., salmon, herring, mackerel) at least twice weekly had a 29% reduction in overall mortality (p <0.05) (Lancet 1989;2:757–761). Recent results from the Nurses’ Health Study, which examined the risk of CHD in 84,688 previously healthy women, found that higher consumption of fi sh and omega-3 fatty acids reduced the risk of cardiac death by up to 45% at 16 years (JAMA 2002;287:1815–1821). Furthermore, there was an inverse relationship between fi sh and omega-3 fatty acid intake and thrombotic stroke—compared to women who ate fi sh <1 time per month, relative risk reductions (RRRs) for women who ate fi sh 1–3 times per month, 1 time per week, 2–4 times per week, and ≥5 times per week were 0.93, 0.78, 0.73, and 0.48, respectively (JAMA 2001;285:304–312). Fish consumption 1–3 times per week also reduced ischemic stroke in men (JAMA 2002;288:3130–3136), and fi sh oil supplements have been shown to incorporate into atherosclerotic plaque and induce changes that enhance plaque stability (Lancet 2003;361:477–485). These studies suggest that the type of fat, not only the amount, affects vascular health.

C. Recommendations. Diet modifi cation should be recommended as part of a comprehensive program to reduce vascular risk. Suggested diets are the TLC diet, the DASH diet, or a Mediterranean-style diet (Tables 10.4, 10.5).



Table 10.4. Basic Components of a Mediterranean Diet

Component Benefi ts

Omega-3-rich1 fi sh 1–2 times per week or omega-3 supplements2

Reduces all-cause mortality and sudden cardiac death post-MI; lowers triglycerides (high doses) and BP; improves insulin resistance; boosts the immune system; may help prevent cancer, arthritis, depression, Alzheimer disease.

Monounsaturated cooking oils (olive, fl axseed, or canola)

Does not increase LDL cholesterol or decrease HDL cholesterol (unlike high saturated fat or high intake of refi ned carbohydrate). “Metabolically neutral” calorie source for people with insulin resistance.

Fresh fruit and vegetables (5–10 servings per day); wide variety

High concentrations of vitamins, minerals, fi ber, and phytochemicals3 help prevent heart disease, stroke, and many types of cancer (colon, stomach, prostate).

Vegetable protein from nuts andbeans 1–2 times per week

Lowers LDL cholesterol; improves digestion; may reduce CHD and certain cancers. Nuts are an excellent source of protein, monounsaturated fat, fi ber, and minerals. Beans contain high-quality protein, fi ber, potassium, and folic acid.4

Limiting saturated fats to <10–20 gm/d Saturated fats increase LDL cholesterol, which promotes atherosclerosis and increases the risk of CHD and stroke. Saturated fats are also linked to certain cancers.

Avoiding trans fats Trans fats are manufactured from vegetable oils and are used to enhance the taste and extend the shelf-life of fast foods, French fries, packaged snacks, commercial baked goods, and most margarines. Trans fats may be more atherogenic than saturated fats. Instruct patients to avoid foods with “hydrogenated” or “partially hydrogenated” vegetable oil as fi rst or second ingredient—these contain trans fats.

Increasing dietary fi ber to 20–30 gm/d Lowers LDL cholesterol; improves insulin resistance; reduces the risk of heart disease and diabetes; protects against colon cancer and possibly breast cancer, irritable bowel syndrome, diverticulitis and hemorrhoids; prevents constipation.



Component Benefi ts

Eating at least one source of high-quality protein with every meal

Produces satiety that lasts longer than do high carbohydrate meals (reduces hunger and cravings); maintains muscle mass and bone strength. Lack of protein increases the risk of breast cancer, diabetes, and osteoporosis.

Adapted from: The Omega Diet, by A. Simopoulos, MD.

1. The typical American diet consists of an unhealthy ratio (>15:1) of omega-6:omega-3 essential fatty acids, favoring excessive production of proinfl ammatory, prothrombotic, and vasoconstrictive mediators of the arachidonic acid cascade (e.g., leukotrienes, thromboxane). Increasing consumption of omega-3 essential fatty acids helps to regulate infl ammation, thrombogenicity, arrhythmogenicity, and vascular tone.

2. Omega-3 supplements may be considered for patients with documented CHD, especially if risk factors for sudden death are present (LV dysfunction, LVH, ventricular dysrhythmias).

3. Phytochemicals are naturally occurring chemicals found in plants—many of them plant pigments—that act as free radical scavengers and protease inhibitors, among others. Examples include lycopene, beta-carotene, indoles, thiocyanates, lutein, resveratrol, ellagic acid, genistein, and allium.

4. Folic acid lowers levels of homocysteine, a by-product of methionine metabolism associated with atherosclerosis.

Table 10.5. How to Incorporate a Mediterranean Diet into Daily Living

Step Choose Go Easy On Avoid

Eat omega-3–rich food 1–2 times per week

Salmon, trout, herring, water-packed tuna, sardines, mackerel, fl axseed, spinach, purslane, fi sh oil supplements.

Raw shellfi sh (due to danger of infection risk, including hepatitis A and B).

Deep-fried fi sh, fi sh sticks, fi sh from seriously contaminated water.

Switch vegetable oils

Flaxseed oil, extra virgin cold-pressed olive oil or canola oil (check the label), mayonnaise made from olive oil or canola oil.

High-oleic saffl ower, sunfl ower, or soybean oil.

Corn oil, saffl ower oil, sunfl ower oil, palm oil, peanut oil, other oils, mayonnaise not from olive oil/canola oil.

Table 10.4. Basic Components of a Mediterranean Diet (cont’d)



Step Choose Go Easy On Avoid

Load up on fresh fruits, and vegetables

Use a wide variety. Fresh fruits: 3–5 daily. Fresh vegetables: 4–6 daily.

Fruit juice (no more than 1–2 cups per day), dried fruit, canned fruit.

Vegetables or fruit prepared in heavy cream sauces or butter.

Add nuts andbeans 1–2 times per week

Soybeans, kidney beans, lentils, navy beans, split peas, other beans, nuts of all kinds.

Heavily salted nuts. Stale or rancid nuts.

Limit saturated fats to 10–20 gm/d; eat at least one source of high-quality protein with every meal

Fish, lean fresh meat with fat trimmed off, chicken and turkey without skin, nonfat or low-fat dairy products (skim milk, yogurt, low-fat cottage cheese), dark chocolate, egg whites or egg substitute, omega-3–enriched eggs.

Processed low-fat meats (bologna, salami, other luncheon meats), 2% milk, “lite” cream cheese, part-skim mozzarella cheese, milk chocolate, egg yolks (3–4 per week).

Prime-grade fatty cuts of meat, goose, duck, organ meats (liver, kidneys), sausages, bacon, full-fat processed meats, hot dogs, whole milk, cream, full-fat cheeses, cream cheese, sour cream, ice cream.

Avoid trans fats Stanol-enriched margarine (Benecol, Take Control).

Commercial peanut butter, water crackers and other crackers that contain no fat, bagels.

Fast food, French fries and other deep-fried food, chips and other packaged snacks, most commercial baked goods, most margarines.

Add more fi ber; aim for 20–30 gm/d

Whole-grain breads and cereals, oats, brown rice, whole-grain pasta, potatoes with skin (baked, boiled, steamed), whole-grain bagels.

Pasta, white rice, mashed instant potatoes, plain bagels, dinner rolls, egg noodles.

Sweetened cereals, white bread, crackers, table sugar, honey, syrup, candy, highly processed foods, especially those with white fl our/sugar.

Drink at least 64 ounces of water per day

Drink 8 glasses of pure, non-chlorinated water per day. Additional drinks: skim milk (up to 4 glasses); pure fruit juice (up to 2 glasses); tea, especially green tea (up to 4 cups); smoothie with plain nonfat yogurt and fresh fruit.

Coffee (regular or decaf), 1% or 2% milk, artifi cially sweetened fruit juice (the tip-off is “corn syrup” in the label), sports drinks, soft drinks, alcohol (no more than 1 drink daily for women, 2 drinks daily for men).

Sugared soft drinks, milkshakes, excess alcohol.

Table 10.5. How to Incorporate a Mediterranean Diet into Daily Living (cont’d)



PHYSICAL ACTIVITY

The Women’s Health Study, a prospective study with 27,055 women participating, investigated the extent of underlying mechanisms accounting for the benefi t of physical activity in reducing cardiovascular events. At 11-year follow-up, they found a risk reduction for cardiovascular disease, including coronary events and strokes, of 27–41%, depending on the extent of physical activity. They computed the proportion of the physical activity–related reduction in cardiovascular disease explained by each of the following risk factors: BP/hypertension, diabetes, lipid profi le, infl ammation/hemostasis (C-reactive protein, fi brinogen, soluble intercellular adhesion molecule 1), body mass index (BMI), and homocysteine. The risk factors investigated accounted for 59% of the reduction. Infl ammatory/hemostatic biomarkers that demonstrate a chronic anti-infl ammatory effect accounted for the largest risk lowering, followed by BP and BMI.

A. Overview. Physical inactivity increases the risk of heart disease and stroke as much as cigarette smoking, yet more than 70% of adults get little or no exercise. All patients should be encouraged to engage in 30–45 minutes of aerobic activity on most days of the week. Regular exercise that increases heart rate to 60–80% of maximal peak heart rate for 30 minutes on all or most days of the week can raise HDL cholesterol levels by up to 30% and can prevent or improve hypertension, insulin resistance and type 2 diabetes, obesity, anxiety, and depression. Regular exercise can also help smokers quit, reduce the risk of MI and stroke by 50% or more, reduce the risk of death post-MI by 25%, and improve functional capacity in patients with claudication from peripheral arterial disease. Physical activity also improves endothelial function and has anti-infl ammatory and hemostatic effects. Noncardiac benefi ts include a lower risk of cancer (colon, prostate, breast) and salutary effects on osteoporosis, arthritis, constipation, insomnia, and postmenopausal symptoms.

B. Amount and Type of Exercise. Traditionally, exercise programs have focused exclusively on aerobic activities such as walking, running, cycling, and swimming. However, data suggest that a strength (weight) training program is an important supplement to aerobic exercise, increasing muscle mass (which increases metabolic rate), improving insulin sensitivity, and helping maintain bone and muscular strength to prevent injuries and disability. Physical activity does not need to be performed in a traditional structured exercise program to provide health benefi ts, and a lifestyle-based exercise program incorporating physical activity into daily living is effective at improving risk factors, weight, and long-term cardiovascular prognosis (JAMA 1999;281:327–334). Physicians should encourage patients to use the stairs, walk whenever possible, garden, play actively with children, etc. Examples of moderate physical activity from the Surgeon General’s Report on Physical Activity and Health (JAMA 1996;276:522) include: • Wash and wax a car, or wash windows or fl oors for 45 minutes • Garden, dance fast (social), or rake for 30 minutes • Walk 1 3/4 miles in 35 minutes (20 min/mile)



• Push a stroller 1 1/2 miles or bicycle 5 miles in 30 minutes • Stairwalk, shovel snow, or jump rope for 15 minutes

The American College of Sports Medicine (ACSM)/AHA recommends 30 minutes of moderate-intensity physical activity (such as brisk walking with noticeably accelerated pulse) 5 days per week or 20 minutes of vigorous-intensity activity (such as jogging) 2 days per week, or combinations of moderate- and high-intensity activity. (Med Sci Sports Exerc 2007;39:1423–1434).

Exercise should not be exhausting, but it does need to be invigorating and should increase heart rate. Individuals are exercising at the right level of intensity if they can talk without gasping for breath but do not have enough breath to sing (e.g., brisk walking at a pace of 3–4 miles per hour, like walking to catch a bus). For motivated patients able and willing to take their pulse, a reasonable goal is to exercise at 60–80% of maximal heart rate (220 – age in years). Additionally, exercise does not need to be done all at one time during the day to receive health benefi ts. The important factor is to accumulate at least 30 minutes of moderate physical activity all or most days of the week (which can be split in three 10-minute blocks). Health benefi ts may plateau at 3500 kcal/week, the equivalent of moderately intense jogging or bicycling for 1 hr/d.

C. Stress Testing. Patients with cardiovascular or respiratory disease, or sedentary patients with multiple CHD risk factors interested in participating in a vigorous exercise program should be considered for stress testing.

WEIGHT CONTROL

A. Overview. An estimated 65% of adults in the US (145 million) are overweight or obese, a number that has more than tripled over the last 2 decades. Over half of these are obese (BMI >30) (http://www.americanheart.org/downloadable/heart/1236358025411OVRWGHT.pdf). Overweight and obesity increase the risk of all-cause mortality, and they increase morbidity from stroke, hypertension, dyslipidemia, type 2 diabetes, CHD, stroke, gall bladder disease, osteoarthritis, sleep apnea, respiratory problems, and cancer (endometrial, breast, prostate, colon). Overweight adults are also more likely to have overweight children. Weight control improves BP, triglycerides, LDL and HDL cholesterol, blood glucose, and hemoglobin A 1c levels in type 2 diabetics. The following information summarizes key recommendations from the NHLBI Clinical Guidelines for the Identifi cation, Evaluation, and Treatment of Overweight and Obesity in Adults (Obesity Res 1998;6:51S–209S; Executive Summary, Arch Intern Med 1998;158:1855–1867).

B. Classifi cation of Obesity. All patients should be stratifi ed by BMI to assess overweight/obesity and by waist circumference to assess abdominal fat content, which identifi es increased risk for CHD independent of BMI and is a criterion for diagnosis of the metabolic syndrome (Table 10.6).



C. Evaluation of Obesity. Patient medications should be reviewed to see if adjustments or substitutions can be made to drugs associated with weight gain, including antidepressants, glucocorticoids, phenothiazines, lithium, cyproheptadine, sulfonylureas, and insulin. It is also important to examine patients for features suggestive of Cushing syndrome (truncal obesity, moon facies, ecchymosis, muscle atrophy, edema, striae, acne, hirsutism, osteoporosis, glucose intolerance, hypokalemia) or hypothyroidism (weakness, fatigue, cold intolerance, constipation, dry skin, bradycardia, hyporefl exia). Patients with suspected sleep apnea (cessation of breathing during sleep, snoring, restless sleep, excessive daytime sleepiness, headaches, memory impairment) should be referred to a specialist.

D. Treatment of Obesity. The treatment of overweight/obesity requires a combination of dietary restriction, increased physical activity, and behavior modifi cation; patients requiring additional measures may benefi t from drug therapy and weight loss surgery (refractory cases). Total caloric intake and energy expenditure (physical activity) should be adjusted to achieve and maintain a desirable body weight (BMI 21–25 kg/m 2 ) and waist circumference (<102 cm in men, <88 cm in women). A reasonable initial goal is to reduce body weight by 10% over 6 months, which typically requires calorie defi cits of 300–500 kcal/d in patients with BMIs of 27–35 kg/m 2 (0.5–1 lb/week) and 500–1000 kcal/d (1–2 lb/week) in patients with BMIs ≥35 kg/m 2 . Further weight loss can be considered once this goal is achieved. Calorie defi cits are best accomplished through a combination of dietary restriction and increased physical activity.

Table 10.6. Classifi cation of Overweight and Obesity

Category BMI* Waist Circumference†

Risk for Type 2 Diabetes, Hypertension, CHD

Underweight <18.5 N or ↑ N

Normal 18.5–24.9 N or ↑ N or ↑

Overweight 25.0–29.9 N↑

IncreasedHigh

Obesity, class I 30.0–34.9 N↑

HighVery high

Obesity, class II 35.0–39.9 N or ↑ Very high

Obesity, class III ≥40.0 N or ↑ Extremely high

BMI = body mass index, CHD = coronary heart disease, N = not elevated.

* Body mass index = weight in kilograms divided by height in meters squared (kg/m2). Estimated BMI using nonmetric measurements = (weight in pounds multiplied by 703) divided by height in inches squared.† Increased waist circumference: men >102 cm (>40 inches); women >88 cm (>35 inches). Increased waist circumference can be a marker for increased risk, even in persons of normal weight.

Adapted from: NHLBI Guideline Report (Obesity Res 1998;6:51S–209S).



1. Dietary Restriction. Calorie defi cits of 500–1000 kcal/d usually require a diet that provides 1000–1200 kcal/d for women and 1200–1500 kcal/d for men. Low-carbohydrate and other “fad” diets may facilitate early weight loss, but these diets are diffi cult to maintain, frequently unhealthy, and often result in diminished self-esteem as weight is inevitably regained. The best approach to diet is to eat smaller portions of a well-rounded (TLC or Mediterranean-style) diet (pp. 80–88).

2. Increased Physical Activity. Increased physical activity is an essential component of an effective weight loss program, leading to calorie defi cits and improvements in cardiovascular risk factors, mood, and self-esteem. Walking is an excellent option for obese patients, initially at 10 minutes/d 3 times weekly, and building to 30–45 minutes/d on most or all days of the week. Ordinary household tasks can also lead to substantial calorie defi cits. A stress test should be considered prior to initiating an exercise program in individuals with known cardiovascular or pulmonary disease, and for sedentary males >40 years or females >50 years with two or more cardiovascular risk factors.

3. Behavior Therapy. It is essential to communicate encouragement, support, and understanding in order to optimize compliance. Other useful behavior modifi cation techniques include self-monitoring (food consumption and exercise), stress management (coping strategies, relaxation techniques, drug therapy), problem solving (coping with urges and cravings), contingency management (rewarding achieved goals), cognitive restructuring (changing unrealistic goals and improving self-image), and social support (positive reinforcement).

4. Drug Therapy (Table 10.7). Pharmacotherapy can be a useful adjunct to dietary restriction, increased physical activity, and behavior modifi cation, but is unlikely to be effective without lifestyle modifi cation. Drug therapy is especially useful for patients with BMIs ≥30 kg/m 2 , or ≥27 kg/m 2 in the presence of other risk factors (hypertension, dyslipidemia, type 2 diabetes, CHD, sleep apnea).

5. Weight Loss Surgery. GI surgery (gastric restriction or bypass) should be reserved for motivated patients with extreme obesity (BMI ≥40 kg/m 2 , or ≥35 kg/m 2 with comorbid conditions) despite nonsurgical intervention. Lifelong medical monitoring and nutritional supplementation with minerals and vitamins are required.



Table 10.7. Antiobesity Drugs Approved by the FDA

Sibutramine HCL (Meridia)Orlistat (Xenical;

also available OTC as Alli)

Drug class Mixed neurotransmitter reuptake inhibitor (norepinephrine, serotonin, dopamine).

Lipase inhibitor; inhibits dietary fat absorption by 30%.

Indications Adjunct to diet in the management of obesity in patients with BMI ≥30 kg/m2, or ≥27 kg/m2 in the presence of other risk factors.

Same as sibutramine.

Dose Initial dose: 10 mg once daily. After 4 weeks, may titrate to 15 mg once daily. Not recommended for children <16 years.

Xenical (120 mg) or Alli (60 mg): one capsule 3 times daily with each main meal containing fat, taken during or up to 1 hr after meals. If a meal is missed or has no fat, the dose can be omitted. Not recommended in children.

Contraindications During or within 2 weeks of MAO inhibitors (e.g., phenelzine, selegiline); concomitant use of centrally acting appetite suppressants; anorexia nervosa. Not recommended in poorly controlled hypertension, CHD, heart failure, arrhythmias, or stroke.

Chronic malabsorption syndrome or cholestasis.

Precautions Not recommended in severe renal impairment or hepatic dysfunction. Check blood pressure and pulse at baseline and regularly during therapy; discontinue or reduce dose for sustained increases in either. Caution if history of seizures (discontinue if occur), hypertension, narrow-angle glaucoma, elderly. Pregnancy (Cat. C); not recommended in nursing mothers.

History of hyperoxaluria; calcium oxalate nephrolithiasis. Weight loss may affect doses needed for antidiabetic drugs (monitor). Pregnancy (Cat. B); not recommended in nursing mothers.



Sibutramine HCL (Meridia)Orlistat (Xenical;

also available OTC as Alli)

Drug interactions Avoid within 2 weeks of MAO inhibitors. Caution with other CNS drugs. Do not coadminister other serotonergic drugs (e.g., sumatriptan, SSRIs, venlafaxine), dihydroergotamine, some opioids (e.g., dextromethorphan, meperidine), lithium, or tryptophan due to possible serotonin syndrome (neuroexcitatory). Do not coadminister other drugs that can raise BP or pulse. Possible interaction with ketoconazole, erythromycin, others metabolized by CYP3A4. Not recommended with excess alcohol.

May decrease absorption of fat-soluble vitamins and beta-carotene; supplement diet with a multivitamin and separate dosing by at least 2 hr. Monitor warfarin (INR), cyclosporine levels.

Side effects Dry mouth, anorexia, insomnia, constipation, headache, increased appetite, dizziness, nervousness, GI upset, increased BP/pulse, mydriasis.

GI effects: oily spotting, fl atus with discharge, fecal urgency, fatty/oily stools, oily evacuation, increased defecation, fecal incontinence.

How supplied 5 mg, 10 mg, 15 mg capsules. 60 mg capsules; 120 mg capsules

SMOKING CESSATION

A. Overview. Tobacco use is one of the most important risk factors for stroke and CHD and is the most preventable cause of death in the U.S. Each year, more than 400,000 deaths are attributable to tobacco use—more than alcohol, heroin, and cocaine abuse; automobile accidents; AIDS; homicide; and suicide combined. Compared to age-matched nonsmokers, persons who smoke 1 pack of cigarettes per day are 14 times more likely to die from cancer of the lung, throat, or mouth; 4 times more likely to die from cancer of the esophagus; twice as likely to suffer an MI or stroke; and twice as likely to die from heart disease or cancer of the bladder. At any age, the risk of death is doubled in smokers compared with nonsmoking age-matched controls. Despite these statistics, few physicians routinely ask patients about cigarette smoking or offer counseling about smoking cessation. The increased vascular risk attributable to smoking returns to baseline

Table 10.7. Antiobesity Drugs Approved by the FDA (cont’d)



soon after cessation of tobacco use, emphasizing the importance of intervention. By 12–18 months, most of the increased risk has disappeared, and by 3–5 years, the risk of vascular events is no different than that of a nonsmoker. For a physician, there is virtually nothing more effective at improving a patient’s long-term prognosis than convincing and helping him or her to stop smoking. If a physician discusses this topic even briefl y with the smoker and makes a strong statement about the medical necessity of discontinuing this habit, a person’s chances of permanent cessation of smoking is doubled. The use of bupropion hydrochloride (Zyban), varenicline (Chantix), and nicotine replacement therapy (NRT) also increases the chances of successful smoking cessation.

B. Guidelines. The US Public Health Service’s most recent guidelines on tobacco cessation provide systematic recommendations for healthcare providers on smoking cessation (http://www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf). The report highlights the importance of a broad-based approach: every patient should be asked about cigarette smoking at every visit, and all smokers should be strongly encouraged to stop and offered NRT and/or varenicline or bupropion hydrochloride. The following strategies were recommended to help patients willing to quit smoking: • Step 1: Systematically identify all tobacco users at every visit. Place tobacco-use

status stickers on all patient charts. • Step 2: Strongly urge all tobacco users to quit. Advice should be clear, strong, and

personalized: “I think it is important for you to quit smoking now, and I can help you.” “As your clinician, I need you to know that quitting smoking is the most important thing you can do to protect your health now and in the future. The clinic staff and I will help you.” Tie tobacco use to the patient’s current health/illness, its social and economic costs, and its impact on children and family.

• Step 3: Determine willingness to make a quit attempt. If the patient is willing to make a quit attempt, assist the patient in quitting or refer the patient to a quit-smoking program. If the patient is unwilling to make a quit attempt, provide a motivational intervention.

• Step 4: Aid the patient in quitting (Tables 10.8, 10.9). • Step 5: Schedule follow-up contact. Follow-up contact should occur soon after

the quit date, preferably during the fi rst week. A second follow-up contact is recommended within the fi rst month. Congratulate success during follow-up contact. If tobacco use has occurred, review the circumstances and elicit a recommitment to total abstinence. Remind the patient that a lapse can be used as a learning experience. Identify problems already encountered and anticipate challenges in the immediate future. Assess pharmacotherapy use and problems, and consider use or referral to more intensive treatment.

For patients who continue to smoke, it is important to recognize interactions between cardiovascular drug therapy and cigarette smoking. These include increased metabolism/ elimination of anticoagulants and beta blockers, possibly requiring higher doses, and decreased diuretic effect due to increased secretion of vasopressin.



Table 10.8. Strategies to Assist Patients Willing to Quit Smoking

Step Strategies for Implementation

Help the patient with a quit plan Set a quit date, ideally within 2 weeks.• Tell family, friends, and coworkers about quitting; request • understanding and support.Anticipate withdrawal symptoms and discuss ways to resist • urges and cravings (clean the house; take a 5-minute walk; do stretching exercises; put a toothpick, cinnamon gum, or lemon drop in mouth; take several slow deep breaths; brush teeth; call a nonsmoking friend and talk).Remove tobacco products from your environment. Throw • out ashtrays. Clean clothes, car, carpets.Learn as much about how to quit smoking as possible. • Useful sources for reading materials include:– American Heart Association, 7272 Greenville Avenue, Dallas,

TX 75231, 800-242-8721; www.americanheart.org– American Cancer Society, 1599 Clifton Road, NE, Atlanta,

GA 30329, 800-227-2345; www.cancer.org– American Lung Association, 1740 Broadway, 14th fl oor,

New York, NY 10019, 800-586-4872; www.lungusa.org– National Cancer Institute, Bethesda, MD 20894,

800-4-CANCER (422–6237); www.nci.nih.gov– For pregnant women: American College of Obstetricians

and Gynecologists, 409 12th Street, SW, Washington, DC 20024, 202-638-5577; www.acog.org

Provide practical counseling Total abstinence is essential. “Not even a single puff after • the quit date.”Identify what helped and hurt in previous quit attempts.• Discuss challenges/triggers and how to overcome them.• Since alcohol can cause relapse, the patient should consider • limiting/abstaining from alcohol while quitting.Patients should encourage housemates to quit with them or • not to smoke in their presence.Provide a supportive clinical environment while encouraging • the patient during the quit attempt: “My offi ce staff and I are available to assist you.”



Step Strategies for Implementation

Recommend approved drug therapy

Recommend the use of fi rst-line drug therapy (Table 10.9) • to all smokers trying to quit, except in special circumstances (e.g., medical contraindications, those smoking fewer than 10 cigarettes/d, pregnant/breastfeeding women, adolescent smokers). If drug therapy is used with lighter smokers (10–15 cigarettes/d), consider reducing the dose of NRT; no dosage adjustment is necessary for sustained-release bupropion hydrochloride.Some studies suggest that bupropion may be more • effective than NRT for achieving permanent cessation of tobacco use, and that some synergism between the two approaches may exist. Because data are insuffi cient to rank-order these medications, initial therapy must be guided by factors such as clinician familiarity with the medications, contraindications for selected patients, patient preference, previous patient experience with a specifi c therapy (positive or negative), and patient characteristics (e.g., history of depression, concerns about weight gain). Sustained-release bupropion hydrochloride and NRT, in particular nicotine gum, have been shown to delay but not prevent weight gain. Sustained-release bupropion hydrochloride and nortriptyline hydrochloride are particularly well suited for patients with a history of depression.Based on meta-analysis, evidence suggests that combining • the nicotine patch with either nicotine gum or nicotine nasal spray increases long-term abstinence rates over those produced by a single form of NRT. The nicotine patch in particular is safe in patients with • cardiovascular disease. However, the safety of these products has not been established for the immediate post-MI period or in patients with severe or unstable angina.Long-term therapy may be helpful for smokers who report • persistent withdrawal symptoms. A minority of individuals who successfully quit smoking use NRT medications (gum, nasal spray, inhaler) long term. The long-term use of these medications does not present a known health risk, and the FDA has approved the use of sustained-release bupropion hydrochloride for long-term maintenance.Clonidine and nortriptyline may be considered when fi rst-• line medications are contraindicated or not helpful.

Adapted from: Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services. Public Health Service. May 2008.

Table 10.8. Strategies to Assist Patients Willing to Quit Smoking (cont’d)



Table 10.9. Drug Therapy for Smoking Cessation*

Therapy Precautions Adverse Effects Dosage and Duration

First-line Bupropion HCl (Zyban)

Contraindicated in patients with history of seizures, eating disorder, MAO inhibitor within 14 days.

Insomnia, dry mouth, seizures.

150 mg every morning for 3 days, then 150 mg bid. Begin treatment 1–2 weeks prior to quit date. Treat for 7–12 weeks. Maintenance therapy may be needed for up to 6 months.

Varenicline (Chantix)

Reduce dosage for patients with impaired creatinine clearance or on dialysis; may impair ability to drive or operate machinery; may cause depressed mood, agitation, suicidality. Elicit a psychiatric history prior to starting.

Nausea, trouble sleeping, abnormal/vivid/strange dreams.

Start varenicline 1 week before the quit date at 0.5 mg/d for 3 days, followed by 0.5 mg bid for 4 days, followed by 1 mg bid for 3 months. Varenicline is approved as maintenance therapy for up to 6 months. Note: Patient should be instructed to quit smoking on day 8, when dosage is increased to 1 mg bid.

Nicotine gum (Nicorette)

Concurrent cigarette smoking is contraindicated due to the risk of nicotine overdose.

Mouth soreness, dyspepsia.

For <25 cigarettes/d: 2-mg gum. For ≥25 cigarettes/d: 4-mg gum. Weeks 1–6: 1 piece every 1–2 hr (at least 9 pieces/d); weeks 7–9: 1 piece every 2–4 hr; weeks 10–12: 1 piece every 4–8 hr. No more than 24 pieces/gum/d.

Nicotine inhaler (Nicotrol inhaler)

Irritation of mouth and throat, coughing, rhinitis.

6–16 cartridges/d for 12 weeks followed by a 6- to 12-week weaning period, if needed. Best effect achieved by continuous puffi ng (20 min).

Nicotine nasal spray (Nicotrol NS)

Nasal irritation. Initial dosing 1–2 doses/hr, increasing as needed for symptom relief. Minimum recommended treatment is 8 doses/d, with a maximum limit of 40 doses/d (5 doses/hr) for 3–6 months. Each dose consists of 2 sprays (1 per nostril) and delivers 1 mg of nicotine to the nasal mucosa.



Therapy Precautions Adverse Effects Dosage and Duration

Nicotine lozenge (Commit)

Nausea, hiccups, and heartburn. 4-mg lozenge also may cause increased rates of headache and coughing.

Available in 2-mg and 4-mg (per piece) doses. The 2-mg lozenge is recommended for patients who smoke their fi rst cigarette more than 30 min after waking, and the 4-mg lozenge is recommended for patients who smoke their fi rst cigarette within 30 min of waking. Dose: 1 lozenge every 1–2 hr during fi rst 6 weeks of treatment, using a minimum of 9 lozenges/d; then decrease lozenge use to 1 lozenge every 2–4 hours during weeks 7–9; then decrease to 1 lozenge every 4–8 hr during weeks 10–12.

Nicotine patch (Nicoderm CQ; Nicotrol)

Local skin reaction, insomnia.

Nicoderm CQ: 21 mg/24 hr (6 weeks), then 14 mg/24 hr (2 weeks), then 7 mg/24 hr (2 weeks). Light smokers (≤10 cigarettes/d) should start with 14-mg dose. Nicotrol patch: 15 mg/24 hr (6 weeks).

Second-line Clonidine

Rebound hypertension.

Dry mouth, drowsiness, dizziness, sedation.

0.15–0.75 mg/d for 3–10 weeks.

Nortriptyline Risk of arrhythmias. Sedation, dry mouth.

75–100 mg/d for 12 weeks.

* See package inserts for additional information. First-line therapies have been approved for smoking cessation by the Food and Drug Administration; second-line therapies have not.

Adapted from: Fiore MC, Jaen CR, Baker TB et al.; Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guidelines. Rockville, MD: US Department of Health and Human Services. Public Health Service. May 2008.

Table 10.9. Drug Therapy for Smoking Cessation* (cont’d)



Chapter 11

Antiplatelet and Antithrombotic Therapy for the Prevention of

Recurrent Ischemic Stroke


Each year, >700,000 Americans have strokes. By 1 year, 5–15% will have had a recurrent stroke; by 5 years, 25–40% will have had a recurrent stroke and 15–25% will have died from a vascular cause. Ischemic stroke accounts for 80–85% of all strokes, and many ischemic strokes are caused by large artery atherothrombosis (Chapter 1). In addition to therapeutic lifestyle changes and control of dyslipidemia, hypertension, and diabetes mellitus, the risk of vascular events in patients with ischemic stroke may be reduced by pharmacologic measures aimed at reducing the risk of atherothrombosis.

ANTIPLATELET THERAPY

A. Atherothrombosis as a Systemic Disease. Atherothrombosis is a generalized process, often involving multiple arterial beds (cerebral, coronary, peripheral) at the same time. Clinical trials show that 25–45% of patients with ischemic stroke have coexistent coronary artery disease, and MI is a leading cause of death long term.

B. Role of the Platelet in Ischemic Stroke. Atherothrombosis is a dynamic, progressive process of arterial injury, thrombosis, and repair. The resulting atherosclerotic plaque progresses through phases, leading to progressive stenosis or acute plaque rupture and intravascular thrombosis, the common underlying mechanism of ischemic stroke, unstable angina, and acute MI (Figure 11.1). Nonobstructive plaques with extensive infl ammation (stimulated by oxidized lipoproteins in the vessel wall), lipid-rich cores, and thin fi brous caps are more prone to ulceration and thrombosis than are long-standing obstructive lesions with extensive calcifi cation and thick fi brous caps comprised of dense collagenous tissue. Platelet adhesion, activation, and aggregation are central to arterial thrombosis, and antiplatelet therapy has been shown to reduce ischemic stroke, nonfatal MI, or vascular death by 25% in high-risk patients (BMJ 2002;324:71–86). Aspirin is the least expensive and most widely studied antiplatelet agent. Compared to aspirin, the thienopyridines (clopidogrel, ticlopidine), which block ADP-mediated platelet activation and subsequent aggregation, reduced the risk of recurrent strokes by 14% in a meta-analysis of four randomized trials (Stroke 2000;31:1779–1784). Dual antiplatelet therapy, utilizing two antiplatelet agents with different mechanisms of action, may be more effective than monotherapy at preventing vascular events. All patients with previous TIA or ischemic stroke due to atherothrombosis should be treated with antiplatelet therapy unless there is a specifi c contraindication. Antiplatelet therapy has not been shown to reduce the risk of initial stroke in those without vascular disease or risk factors for atherosclerosis.

C. Antiplatelet Monotherapy 1. Aspirin. Aspirin exerts its antiplatelet effects by blocking the formation of

thromboxane A 2 through irreversible acetylation of platelet cyclooxygenase, decreasing

the likelihood that an occlusive thrombus will form at the site of an infl amed, ulcerated atherosclerotic plaque. Enzyme inhibition lasts for the lifespan of the platelet (~10 days). Aspirin does not prevent atherosclerosis, platelet adhesion, or platelet aggregation in response to ADP, collagen, thrombin, or epinephrine. The Antithrombotic Trialists’ Collaborative (ATC) overview of randomized trials of antiplatelet therapy, comprising



more than 210,000 patients in 287 studies, found that aspirin reduced the risk of vascular events in high-risk patients, including recurrent stroke, by 22% (BMJ 2002;324:71–86). The optimal dose of aspirin is not known, although ATC found that doses of 75–150 mg seem to be as effective as higher doses for long-term therapy. A 1999 meta-analysis (Neurology 1999;53(7):S25) of more than 9000 patients also found no increased benefi t to aspirin with higher doses. Doses in excess of 325 mg/d are associated with increased risk of GI bleeding in a dose-dependent fashion. Enteric-coated or buffered forms of aspirin are just as likely to cause GI bleeding as is soluble aspirin. Low-dose aspirin (75–162 mg) should be considered for patients with a history of serious bleeding, especially from the GI tract, and aspirin should not be given for a minimum of 24 hours after thrombolytic therapy for ischemic stroke, due to an increased risk of intracranial bleeding. A signifi cant minority of patients with coronary artery disease or prior stroke are aspirin resistant (Circulation 2000;18:11–418; Thromb Haemost 2002;88:711–715), which may increase the risk of recurrent vascular events (Circulation 2002;105:1650–1655; Thromb Res 1993;71:397–403). While no randomized clinical trial has evaluated optimal therapy for patients with stroke who are already taking aspirin, it is reasonable that patients who have a recurrent TIA or ischemic stroke while on aspirin be treated with clopidogrel or dual antiplatelet therapy.

FRESH CLOT

Vessel Wall

PlateletEvents

Activation ofCoagulation

Cascade

Loosely adherentplatelet aggregates

Cross-linkedfibrin polymer

Fibrin

Thrombin

Tissue factor

PLAQUE RUPTURE

Aggregation

Activation

Adhesion

Figure 11.1. Pathophysiology of Acute Ischemic Stroke

Intravascular thrombosis is central to the pathogenesis of acute ischemic stroke. Plaque rupture exposes circulating blood to vessel wall contents, which rapidly induces clot formation via activation of two complementary systems: platelets and the coagulation cascade. The mechanism of action of antiplatelet agents is shown in Figure 11.2.

Chapter 11. Antiplatelet and Antithrombotic Therapy 103


2. Clopidogrel. Clopidogrel is an inhibitor of ADP-induced platelet activation and subsequent aggregation, acting by irreversible binding to the platelet P2Y

12 receptor

and by the subsequent ADP-mediated activation of the platelet GP IIb-IIIa receptor complex. Clopidogrel irreversibly modifi es the platelet ADP receptor, so that platelets exposed to clopidogrel are affected for the remainder of their lifespan. Compared to

Figure 11.2. Mechanism of Antiplatelet Therapy

Platelet

Platelet Aggregation

Platelet

Platelet Activation

Platelet Adhesion

PlateletPharmacologic Interventions

AA

Heparin, direct thrombin inhibitors1

Thienopyridines (clopidogrel/ticlopidine)2

Aspirin, COX1 inhibitors3

GP IIb-IIIa receptor inhibitors

to disrupted endothelium or ruptured plaque

von Willebrand factorGP Ib integrin

Fibrinogen

Thrombin1

ADP CollagenSerotonin Epinephrine

Shear ratevia GP IIb-IIIa and fibrinogen

4

2

3 TXA2

GP IIb-IIIaintegrin

4

AA = arachadonic acid, ADP = adenosine diphosphate, COX = cyclooxygenase, GP = glycoprotein, TXA

2 = thromboxane A

2. Plaque rupture induces platelets to proceed through adhesion, activation, and

aggregation. Platelet adhesion is initiated by the binding of von Willebrand factor, an adhesive glycoprotein released from the injured vessel wall, to the platelet glycoprotein (GP) Ib receptor. Platelets are exposed to multiple agonists at the same time (ADP, TXA

2, epinephrine, thrombin, serotonin, collagen), which trigger a

series of events within the platelet, including increased cytosolic calcium, cell shape changes, phosphorylation of proteins, release of granules and lysosomes, arachidonic acid metabolism, and conformational change in the GP IIb-IIIa receptor complex so that it becomes expressed and active on the platelet surface. 50,000–80,000 GP IIb-IIIa receptors reside on the surface of activated platelets. Fibrinogen is the most important ligand of the GP IIb-IIIa receptor and can bind two GP IIb-IIIa receptors simultaneously, creating a molecular platelet-to-platelet bridge. Aspirin blocks the formation of thromboxane A

2 through irreversible

acetylation of platelet cyclooxygenase. Clopidogrel and ticlopidine irreversibly modify the platelet ADP receptor, interfering with binding of ADP to its receptor and ADP-mediated activation of the GP IIb-IIIa receptor. Dipyridamole is a phosphodiesterase inhibitor that raises platelet levels of cyclic AMP. Aspirin and the thienopyridines (clopidogrel, ticlopidine) have their major mode of action directly on the platelet. In contrast, dipyridamole and cilostazole have an important endothelial activity and inhibit attachment of the platelet to the endothelium. Both dipyridamole and cilostazole promote vasodilatation, and headache accompanies their fi rst use.

Adapted from: Peterson M, Dangas G, Fuster V. Atherosclerosis and thrombosis. In: The Manual of Interventional Cardiology, 3rd ed., Royal Oak, MI: Physicians' Press, 2001.



ticlopidine, another thienopyridine derivative, clopidogrel has a longer duration of action, faster onset of action, and is better tolerated with fewer adverse hematologic effects (Thromb Haemost 1996;76:939–943; Platelets 1993;4:252–261). In the Clopidogrel vs. Aspirin in Patients at Risk for Ischemic Events (CAPRIE) trial, 19,185 patients with atherosclerotic vascular disease (MI within 35 days, ischemic stroke within 6 months, or established peripheral arterial disease) were randomized to clopidogrel (75 mg/d) or aspirin (325 mg/d). At a mean follow-up of 1.9 years, clopidogrel was more effective than aspirin at reducing the combined endpoint of stroke, MI, or vascular death (RRR, 8.7%; p = 0.043) (Lancet 1996;348:1329). However, patients enrolled in the CAPRIE study following stroke had no signifi cant decrease in vascular events. Clopidogrel-treated patients developed slightly fewer bleeding complications, and there was no difference in the incidence of severe neutropenia between groups. In a meta-analysis analysis of four randomized trials, thienopyridines (clopidogrel, ticlopidine) reduced the relative risk of recurrent stroke by 14% compared to aspirin (Stroke 2000;1779–1784). Clopidogrel is approved for the reduction of atherothrombotic events (MI, ischemic stroke, vascular death) in patients with recent MI, recent stroke, or established peripheral arterial disease, and is an excellent choice for patients with cerebrovascular disease who require antiplatelet therapy. The safety profi le of clopidogrel is similar to aspirin and better than ticlopidine, with a rare incidence (~4 per million) of thrombotic thrombocytopenic purpura (N Engl J Med 2000;342:1773–1777). Combination antiplatelet therapy with aspirin plus clopidogrel has been shown to reduce vascular events in patients with ischemic heart disease compared to aspirin alone but has not been shown to be more effective than clopidogrel monotherapy in patients with stroke or TIA. In the MATCH study of more than 6000 patients with TIA or stroke randomized to clopidogrel (75 mg) or clopidogrel plus aspirin (75 mg), combination therapy did not reduce vascular events, but signifi cantly increased the rate of hemorrhage.

3. Ticlopidine. Ticlopidine is similar to clopidogrel in structure and mechanism of action and has been shown to reduce the risk of recurrent stroke by >20% compared to aspirin in CATS and TASS but not in AAASPS (pp. 145–148). Effi cacy is limited by adverse effects, including rash, diarrhea, neutropenia (2.3–3.4%), thrombocytopenia, and thrombotic thrombocytopenic purpura (1 in 2000–4000 patients) (Ann Intern Med 1998;128:541–544). Because of its superior safety profi le, clopidogrel has replaced ticlopidine in the management of patients with atherothrombotic disease.

D. Combination Antiplatelet Therapy. Ex vivo platelet aggregation studies and clinical trials indicate that utilizing two antiplatelet agents with different mechanisms of action may be more effective at preventing platelet aggregation and vascular events than single-agent therapy. The combination of low-dose aspirin and high-dose extended-release dipyridamole (marketed as Aggrenox) has been shown to be more effective than low-dose aspirin alone in preventing stroke in patients with stroke or TIA. However, the combination of low-dose aspirin and clopidogrel did not prevent more stroke than clopidogrel alone, and was associated with a signifi cant increase in the number of major intracranial and extracranial hemorrhages.



1. Combination aspirin plus dipyridamole. Among 10,404 patients in 25 trials comparing aspirin plus dipyridamole vs. aspirin alone, combination therapy resulted in a nonsignifi cant 6% reduction in vascular events (Antithrombotic Trialists’ Collaboration: BMJ 2002;324:71–86). In the second European Stroke Prevention Study (ESPS-2), 6602 patients with ischemic stroke (76%) or TIA (24%) within 3 months were randomized to twice daily dosing of low-dose aspirin/ extended-release dipyridamole (25 mg/200 mg), either agent alone, or placebo. At 24 months, combination therapy reduced the risk of stroke by 23.1% compared to aspirin alone (p = 0.006), by 24.7% compared to dipyridamole alone (p = 0.002), and by 37.0% compared to placebo (p <0.001) (J Neurol Sci 1996;143:1–13). Aspirin plus dipyridamole did not, however, reduce the risk of MI or death compared to either agent alone. The most common side effect of dipyridamole is headache. The currently available preparation (aspirin 25 mg plus dipyridamole 200 mg) is given as one capsule twice daily and is approved for the prevention of recurrent stroke in patients with TIA or prior atherothrombotic ischemic stroke. The low dose of aspirin (50 mg/d) in this preparation does not provide adequate protection against recurrent MI or angina pectoris.

2. Combination aspirin plus clopidogrel. This combination has been shown to reduce vascular events in three randomized cardiovascular trials, but not in patients with stroke.

a. Treatment of acute coronary syndromes. In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12,562 patients with unstable angina or non-ST-elevation MI were treated with aspirin (75–325 mg/d) and randomized to clopidogrel (300 mg loading dose followed by 75 mg/d) or placebo for up to 12 months (average, 9 months). Patients receiving clopidogrel had a highly signifi cant 20% reduction in the primary composite endpoint of cardiovascular death, MI, or stroke (9.3% vs. 11.5%, p <0.002) (N Engl J Med 2001;345:494–502). Benefi ts were independent of concomitant cardiovascular medications, including ACE inhibitors and lipid-lowering therapy. Among 506 patients with prior stroke, a trend toward reduction in the primary endpoint was observed in the clopidogrel group (17.9% vs. 22.4%; RRR, 26%; 95% CI, 0.50–1.10). There was a 1% absolute increase in major bleeding complications with clopidogrel, but there was no increase in fatal bleeding. (Bleeding was lower in patients receiving <100 mg/d aspirin compared to patients receiving >300 mg/d.) In CURE, 2658 of 12,562 patients underwent percutaneous coronary intervention (PCI). Patients received study drug (clopidogrel or placebo) for a median of 10 days prior to PCI, open-label clopidogrel for 2–4 weeks after PCI, then resumption of study drug for a mean of 8 months. Clopidogrel resulted in an overall (before and after PCI) reduction in cardiovascular death or MI of 31% (8.8% vs. 12.6%, p = 0.002) (Lancet 2001;358:527–533). Based on these results, the ACC/AHA guidelines were updated to recommend that patients with acute coronary syndrome (unstable angina or non-ST-elevation MI) receive clopidogrel for 9 months in addition to aspirin and other standard therapies (J Am Coll Cardiol 2002;40:1366–1374).



b. Adjunct to elective PCI for patients with coronary artery disease. In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, 2116 patients undergoing elective PCI were randomized to long-term (1-year) therapy with aspirin plus clopidogrel vs. short-term (4-week) therapy with aspirin plus clopidogrel followed by aspirin alone. At 1 year, long-term therapy resulted in a 26.9% relative reduction in the combined endpoint of death, MI, or stroke (p = 0.02) (JAMA 2002;288:2411–2420). Also noted was a nonsignifi cant 25% RRR in stroke.

c. In the Clo pidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) (Lancet 2005;366:1607–1621) 45,852 patients within 24 hours of suspected acute MI were randomized to clopidogrel (75 mg/d) or placebo; all patients received aspirin (162 mg/d). 93% of the patients had ST elevation or bundle-branch block, and 7% had ST depression. Duration of treatment was until discharge or up to 4 weeks in the hospital. Patients receiving clopidogrel in addition to aspirin had a 9% lower risk of death; reinfarction of stroke (9.2% vs. 10.1%, p = 0.002).

d. Prevention of recurrent stroke and other vascular events in patients with recent TIA or stroke. The Management of ATherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic stroke (MATCH) trial (Lancet 2004;364(9431):331–337) compared aspirin (75 mg/d) plus clopidogrel (75 mg/d) to clopidogrel alone (75 m/d) in 7599 patients with recent (<3 months) TIA or ischemic stroke and at least one additional vascular risk factor (prior ischemic stroke, prior MI, angina pectoris, peripheral arterial disease, or diabetes). For the combined endpoint MI, stroke, vascular death, or rehospitalization for ischemic events during 18 months of follow-up, there was no signifi cant difference between clopidogrel monotherapy and clopidogrel plus aspirin; however, for patients receiving the combination of clopidogrel and aspirin, the incidence of life-threatening bleeds doubled from 1.3% to 2.6%. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) (N Engl J Med 2006;354:16) trial evaluated the combination of aspirin (75–162 mg/d) plus clopidogrel (75 mg/d) vs. aspirin alone (75–162 mg/d) in 15,603 patients at high atherothrombotic risk (primary and secondary prevention), including patients with previous TIA, ischemic stroke, or carotid stenosis. The study failed to fi nd benefi t for the combination of clopidogrel and aspirin for the primary endpoint (a composite of cardiovascular death, nonfatal MI, or nonfatal stroke), but did fi nd benefi t when hospitalizations for ischemic events were added to the primary endpoint. The cardiovascular death rate was signifi cantly higher for patients treated with clopidogrel plus aspirin vs. clopidogrel alone; however, patients with clinically evident atherothrombosis treated with clopidogrel plus aspirin had signifi cantly fewer primary outcome events than did patients treated with aspirin alone. In summary, there was no compelling benefi t to adding clopidogrel to aspirin in this patient population; by some measures, there may be harm.



The ACTIVE (Atrial fi brillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events) trials compared the combination of low-dose aspirin plus clopidogrel to warfarin (ACTIVE W; Lancet 2006;367(9526):1903–1912) or aspirin (ACTIVE A; NEJM March 31, 2009; available online) in patients with atrial fi brillation. Active W enrolled 6716 patients with atrial fi brillation and stroke risk factors, randomized to warfarin with an INR goal of 2.0–3.0, or clopidogrel (75 mg) plus low-dose aspirin (75–100 mg); the study was stopped early because of a signifi cant 44% increase in vascular events among patients randomized to the clopidogrel/aspirin arm. In Active A, 7554 patients with atrial fi brillation and stroke risk factors who were considered unsuitable for warfarin were randomized to aspirin (75–100 mg/d) or aspirin plus clopidogrel; for patients receiving clopidogrel in addition to aspirin, there was a 0.8% absolute reduction in major vascular events, including a 0.9% reduction in stroke. However, a 0.7% annual increase in the risk of hemorrhage was reported.

e. Comparative trial of clopidogrel vs. combination low-dose aspirin and extended-release dipyridamole. The Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) trial (N Engl J Med 2008;359:12) randomized 20,332 patients to receive either clopidogrel (75 mg/d) or low-dose aspirin (25 mg bid) plus extended-release dipyridamole (200 mg bid). (This trial used a 2 � 2 factorial design, in which the angiotensin-receptor blocker telmisartan was compared to placebo; results of this arm will be discussed in Chapter 12.) After 2.5 years of follow-up, the recurrent stroke rate was 9.0% in patients treated with the combination aspirin/dipyridamole regimen, and 8.8% for patients treated with clopidogrel. Patients treated with the aspirin/dipyridamole combination (4.1% vs. 3.6%) had more hemorrhagic complications, but this was not statistically signifi cant. The study failed to meet its primary endpoint of noninferiority of aspirin/dipyridamole compared to clopidogrel. Nonetheless, given the size and power of the PRoFESS study, it is reasonably clear that no major clinical differences exist between these two therapies in terms of effi cacy.

E. Summary (Figure 11.3). All patients with prior ischemic TIA or stroke due to atherothrombosis should receive antiplatelet therapy unless there is a specifi c contraindication. Monotherapy with aspirin (75–325 mg/d), clopidogrel (75 mg/d), or ticlopidine (250 mg bid) reduces the risk of MI, stroke, or cardiovascular death by ~25% compared to placebo. Aspirin is the least expensive agent, while the thienopyridines (clopidogrel and ticlopidine) are more potent antiplatelet agents than aspirin. (Clopidogrel is better tolerated than ticlopidine, with fewer adverse effects.) Compared to aspirin alone, dual antiplatelet therapy with low-dose aspirin plus extended-release dipyridamole (25 mg/200 mg bid) was more effective at reducing recurrent stroke in ESPS-2, but it did not reduce the risk of MI or death compared to either agent alone. The PRoFESS study failed to fi nd a difference between clopidogrel and the combination of low-dose aspirin and extended-release dipyridamole for any primary or secondary endpoints. Lastly, regardless of effi cacy, there appears to be a trend toward increased hemorrhage rates for stroke patients on dual antiplatelet therapy. Multiple clinical trials—PRoFESS, MATCH, ACTIVE A, and CURE—have shown a higher hemorrhagic complication rate for combination antiplatelet therapy compared to monotherapy.



ANTITHROMBOTIC THERAPY

Atrial fi brillation increases the risk of death twofold compared to patients in normal sinus rhythm, largely from increased risk of stroke or systemic emboli (Arch Intern Med 1995;155:469–473). Adjusted-dose warfarin (INR 2.0–3.0) has been shown to reduce the risk of stroke from atrial fi brillation by 68% (Arch Intern Med 1994;154:1449). All patients with rheumatic atrial fi brillation and without contraindications should receive warfarin long term. As the risks of stroke and bleeding from warfarin vary greatly, risk stratifi cation can help decide whether patients with nonrheumatic atrial fi brillation should receive aspirin or

Internal carotidartery disease

Ischemic Stroke or TIA

Stenosis.70%

Stenosis,50%

Warfarin long term(INR 2.023.0;

3.024.5 for prostheticheart valve)*

Warfarin contraindicatedor recurrent symptoms

despite warfarin

CEA†1antiplatelet‡

Men: CEA†1 antiplatelet‡

Women: Antiplatelet‡ Antiplatelet‡

Antiplatelet‡

Stenosis50269%

Cardiogenicembolism

Figure 11.3. Antiplatelet and Antithrombotic Therapy for Secondary Prevention of Ischemic Stroke

* Consider aspirin (325 mg/d) instead of warfarin for lone atrial fi brillation (age <60 years and no hypertension, heart failure, mitral valve disease, prior embolism).

† CEA can reduce the annual risk of stroke by 50% (from 2%/year to 1%/year) if performed by a surgeon, with morbidity/mortality rate <3%. Carotid stenting may be considered in select cases.

‡ Aspirin (325 mg/d), clopidogrel (75 mg/d), or combination low-dose aspirin plus extended-release dipyridamole (25 mg/200 mg bid). Consider combination aspirin (81–325 mg/d) plus clopidogrel (75 mg/d) for high-risk patients, especially those at increased risk of cardiac events. For plaque disease, some studies suggest benefi t with lower-dose aspirin (81–165 mg/d).



warfarin (Table 11.1). Warfarin is sometimes used in patients not undergoing revascularization of severe stenosis in the internal carotid or vertebral arteries and in patients with severe stenosis or recent occlusion of intracranial arteries. Antithrombotic therapy is posited to be effective in conditions that promote the formation of red (erythrocyte-fi brin) clots, such as stasis within the heart, large protruding aortic atheromas, and severe stenosis or occlusion of large arteries. The routine addition of aspirin to low-dose warfarin has not been shown to confer any signifi cant benefi t over standard warfarin dosing with respect to stroke preven-tion. Recently, in SPORTIF-III (randomized, open label) and SPORTIF-V (randomized, double blinded), ximelagatran, an oral direct thrombin inhibitor, was shown to be at least as safe and effective as warfarin at preventing stroke in patients with nonvalvular AF, without the need

Table 11.1. Stratifi cation of Nonrheumatic Atrial Fibrillation

Biannual Stroke Risk Patient Features

2001 ACCP Recommendations*

NNT to Prevent 1 Stroke

Low (~2%) Age <65, no major risk factors.†

Aspirin 227

Low moderate (~3%) Age 65–75, no major risk factors.†

Aspirin or warfarin (INR 2–3)

Aspirin: 152 Warfarin: 54

High moderate (~5%) Age 65–75, no major risk factors† but with either diabetes or coronary disease.

Warfarin (INR 2–3) 32

High (~12%) Age <75 with hypertension, LV dysfunction, or both, or age >75 without other risk factors.†


Very high (~20%) Age >75 with hypertension, LV dysfunction, or both, or any age and prior stroke, TIA, or systemic embolism.


NNT = number needed to treat* Adapted from 2001 American College of Chest Physicians recommendations, which apply only to patients without contraindications to the suggested therapies.† Major risk factors include: prior stroke, systemic embolism, or TIA; hypertension; poor LV function (clinical history of heart failure or ejection fraction <50% on echocardiogram).Modifi ed from: JAMA 2002;288:1388–1395.



for monitoring (p. 144). However, there were concerns about the noninferiority endpoints of the SPORTIF studies, as well as hepatotoxicity, and the FDA did not approve the use of ximelagatran in the U.S. (see J Am Coll Cardiol 2005;46;1986–1995). The ACTIVE studies (discussed above, section 2d) evaluated the use of clopidogrel plus aspirin in patients with atrial fi brillation. In ACTIVE W, warfarin with an INR goal of 2.0–3.0 proved superior to clopi-dogrel/aspirin combination therapy in preventing new strokes; in ACTIVE A, patients (who were deemed unsuitable for warfarin therapy) had fewer vascular events while treated with clopidogrel and aspirin compared to aspirin monotherapy, but this benefi t was counterbal-anced by an increased major hemorrhage rate.



Chapter 12

Control of Hypertension


Hypertension affects 1 billion people worldwide, including 50 million Americans. The World Health Organization reports that suboptimal BP is responsible for 62% of cerebrovascular disease and 49% of ischemic heart disease, and is the number one attributable risk factor for death throughout the world. For individuals aged 55–65 years without hypertension at baseline, the risk of developing hypertension is 90%, if they live into their 80s. (JAMA 2002;287:1003–1010). More than 90% of hypertension is idiopathic (essential), while 5–10% can be ascribed to an identifi able cause (secondary hypertension). Essential hypertension is caused by increased vascular reactivity and/or the inappropriate renal retention of salt and water. Over many years, hypertension leads to accelerated atherosclerosis in large vessels, obliterative changes and/or thinning and rupture of small vessels, and increased workload on the heart.

Hypertension is the most important modifi able risk factor for stroke. Severe hypertension increases the risk of stroke 7-fold, and borderline hypertension increases the risk 1.5–fold. Observational studies involving more than 1 million subjects show that death from both heart disease and stroke increases linearly from levels as low as 115 mmHg SBP and 75 mmHg DBP. For every 20 mmHg systolic or 10 mmHg diastolic increase in BP, there is a doubling of mortality from both ischemic heart disease and stroke. Data from the Framingham Heart Study indicate that BP values between 130–139/85–89 mmHg are associated with a more than doubling of relative risk from cardiovascular disease as compared with those with BP levels below 120/80 mmHg (Figure 12.1). An average reduction of 9/5 mmHg can reduce the risk of stroke by 35–45% within 2–3 years of therapy (Lancet 2001;358:1033–1141; Lancet 2000;355:865–872; Lancet 1991;338:1281; Lancet 1990;335:827), and benefi ts extend to patients >80 years of age (Lancet 1999;353:793–796). Proper treatment reduces by 30% the incidence and fatality from CHD, heart failure, and kidney disease. Despite these benefi cial effects, hypertension is grossly underdiagnosed and undertreated: only 68% of adults with hypertension are aware of their condition, only 50% are receiving medications, and only 27% of treated patients have BP <140/90 mmHg. Thiazide diuretics, beta blockers, ACE inhibitors, and long-acting dihydropyridine calcium antagonists have all been shown to reduce the risk of stroke (CMAJ 1999;161:25–32; JAMA 1997;277:739–745; Lancet 2000;356:1955–1965; Am J Med 2001;111:553–558).

DIAGNOSIS AND EVALUATION OF HYPERTENSION

Hypertension is defi ned by an SBP �140 mmHg ± DBP �90 mmHg, based on the average of two or more readings at two or more visits after the initial screen. A single recording may be suffi cient if SBP is �210 mmHg or DBP is �120 mmHg, especially if symptoms are present, but even very high elevations in BP may occur transiently during extreme stress or acute illness. BP �135/85 mmHg outside the physician’s offi ce should also be considered elevated.

Because of the increased risk of vascular complications associated with levels of BP previously considered to be normal, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure introduced a



General Population: ,140/90 mmHgDiabetes mellitus or chronic kidney disease: ,130/80 mmHg

Optimize dosages or add additional drugs until BP goal is achievedConsider referral to a hypertension specialist

High Blood Pressure

Not at Blood Pressure Goal

Initiate drug therapy based on patient characteristics, coexistent conditions, and BP levelStart two drugs in most patients with BP .20/10 mmHg above target BP

Initiate Drug Therapy*

Not at Blood Pressure Goal

Begin or Continue Lifestyle Modifications

Lose weight if overweightLimit alcohol to no more than 2 drinks/d (1 oz or 30 mL of ethanol}24 oz beer, 10 ozwine, or 3 oz 80-proof whiskey) in most men and no more than 1 drink/d in womenand lighter-weight personsIncrease aerobic physical activity to 30245 minutes most days of the week

Reduce sodium intake to #100 mmol/d (2.4 gm/d sodium or 6 gm/d sodium chloride)Maintain adequate intake of dietary potassium (~90 mmol/d), calcium, magnesiumStop smoking for overall cardiovascular healthIncrease dietary intake of fruits, vegetables, and low-fat dairy with a reduced contentof saturated fat and total fat

Figure 12.1. Treatment of Hypertension

* Drug therapy is often initiated concurrently with lifestyle modifi cation in high-risk patients. Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JAMA 2003;289:2560–2572).

new classifi cation that includes the term “prehypertension” for those with BPs ranging from 120–139 mmHg systolic and/or 80–89 mmHg diastolic (Table 12.1). The purpose of the new term is to allow for identifi cation of patients in whom early intervention (mainly lifestyle modifi cation) could reduce BP, decrease the rate of progression of BP to hypertensive levels with age, or prevent hypertension and its complications entirely. Stage 3 hypertension was also combined with Stage 2 in the JNC VII classifi cation scheme, to refl ect the urgency of treating these patients and the absence of difference in treatment for them.

Chapter 12. Control of Hypertension 115


A. Proper BP Measurement Technique. Improper technique can result in the overdiagnosis or underdiagnosis of hypertension (Table 12.2). Up to 50% of patients found to have elevated BP on initial exam will not have persistently elevated BP. BP measurements should be repeated over weeks to months to ensure that hypertension is present and persistent. 1. Have the patient sit quietly for at least 5 minutes in a chair with back supported and

arm supported at heart level, either passively or by a table. Standing, sitting unsupported, or actively holding the arm at heart level can raise BP by 5–10 mmHg.

2. Ensure no caffeine or smoking within the last 30–60 minutes and no recent use of exogenous adrenergic stimulants (e.g., phenylephrine in nasal decongestants); these can elevate BP.

3. Use an appropriate size cuff. The bladder should encircle ~80% of the arm circumference. If arm circumference is >33 cm, a large cuff must be used to avoid artifi cially high readings.

4. Apply the cuff so that the lower margin is 2–3 cm above the antecubital space. Ensure the middle of the bladder overlies the brachial artery pulse.

5. Infl ate the bladder quickly ~20 mmHg above systolic pressure (i.e., disappearance of radial pulse). Ensure the arm cuff is at the level of the heart.

6. Defl ate the bladder at 2–3 mmHg/sec, recording pressures at both the beginning and disappearance of the Korotkoff sounds. More rapid defl ation can underestimate SBP and overestimate DBP.

7. Wait 1–2 minutes and repeat the measurement. A third reading should be obtained if the variance exceeds 5 mmHg.

Table 12.1. JNC VII Classifi cation of Blood Pressure in Adults

Blood Pressure Classifi cation SBP in mmHg DBP in mmHg

Normal <120 And <80

Prehypertension 120–139 Or 80–89

Stage 1 Hypertension 140–159 Or 90–99

Stage 2 Hypertension ≥160 ≥100

Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, 2004. National Heart, Lung, and Blood Institute, the National Institutes of Health and the US Department of Health and Human Services.



8. Other tips. If pressures differ between arms, the higher reading should be used. If arm pressure is elevated, a leg pressure should be measured, especially in younger patients, to detect coarctation of the aorta. For patients with atrial fi brillation or frequent extrasystoles, the average of several measurements should be recorded. It is important to check for orthostatic changes before and after initiating/increasing drug therapy, especially in diabetics and the elderly, and in patients with lightheadedness or dizziness. Ambulatory monitoring and frequent home measurements are often helpful in quantifying BP abnormalities.

Table 12.2. Factors Affecting Blood Pressure Recordings

Overestimates True BP Underestimates True BP No Effect on BP

ExamineeSoft Korotkoff sounds

(DBP effect)PseudohypertensionWhit-coat reactionParetic arm (stroke)Pain, anxietyAcute smokingAcute caffeineAcute ethanolDistended bladderTalking

ExaminerExpectation biasImpaired hearing

ExaminationCuff too narrow/looseCuff not centeredCuff over clothingElbow too lowShort rest periodBack unsupportedArm unsupportedToo slow/fast defl ation

Setting, equipmentNoisy environment Leaky bulb valveBlocked manometer ventsCold hands/stethoscope

ExamineeSoft Korotkoff sounds

(SBP effect)Recent mealMissed auscultatory gapHigh stroke volume

ExaminerReading to next lowest

5/10 mmHgExpectation biasImpaired hearing

ExaminationNoisy environmentLeft vs. right armLong rest periodElbow too highToo rapid defl ationExcess bell pressure

Setting, equipmentNoisy environmentFaulty aneroid deviceLow mercury levelLeaky bulb

ExamineeMenstrual phaseChronic caffeine Phenylephrine nasal sprayCuff self-infl ationDiscordance in sex or race

Examiner Discordance in sex or race

ExaminationThin shirtsleeve under cuffBell vs. diaphragmCuff infl ation Hour of dayRoom temperature

Adapted from: JAMA 1995;273:1211–1218.



B. Excluding Conditions Leading to Overdiagnosis of Hypertension 1. White-Coat Hypertension. White-coat hypertension is defi ned as hypertension

that occurs only during doctors’ offi ce visits and accounts for �20% of apparent hypertension (JAMA 1988;259:225–228). The diagnosis should be suspected in patients with persistent elevations in BP but without evidence of target organ damage and is confi rmed by ambulatory and home monitoring with measurements consistently �135/85 mmHg. Over 10 years, white-coat hypertension is associated with little if any increased risk of end-organ damage (Circulation 1998;98:1892–1897). Treatment consists of lifestyle modifi cations and close follow-up. Drug therapy is reserved for patients with persistent hypertension.

2. Pseudohypertension. Pseudohypertension occurs when the BP cuff pressure needed to completely compress an extremely calcifi ed and rigid brachial artery greatly exceeds IA pressure; this results in artifi cial elevations in BP. Pseudohypertension should be suspected in elderly patients with generalized atherosclerosis; in patients whose radial artery can still be palpated when cuff pressure exceeds auscultatory SBP (Osler sign); and in patients with elevated BP who develop hypotensive symptoms on drug therapy.

C. Assessing Target Organ Damage. All hypertensive patients should be evaluated for target organ damage and clinical cardiovascular disease, including cerebrovascular disease (TIAs, stroke); cardiovascular disease (angina, prior MI or coronary revascularization, heart failure, LVH); retinopathy (hemorrhages, exudates, papilledema); nephropathy (increased creatinine, proteinuria, microalbuminuria); peripheral artery disease (claudication, aneurysm, absent or diminished arterial pulses).

D. Detecting Secondary Hypertension. Hypertension ascribed to an identifi able cause represents 5% of the total hypertensive population. Indications for work-up include: (1) clinical features suggesting a secondary cause (Table 12.3); (2) resistance to triple-drug therapy; (3) BP worsening after a period of good control; (4) accelerated or malignant hypertension; or (5) negative family history with DBP >110 mmHg.

Table 12.3. Causes of Secondary Hypertension

Cause Features

Renovascular hypertension

Age <30 years or >60 years, DBP �120 mmHg, recent onset or exacerbation of hypertension (<2 years), malignant hypertension, systolic-diastolic bruit in upper abdomen, refractory hypertension, acquired resistance to antihypertensive therapy (especially in elderly patients), deterioration in renal function after ACE inhibitors or angiotensin II receptor blockers.

Pheochromocytoma Spells of headache, palpitations, tachycardia, inappropriate perspiration, tremor, pallor; unusually labile BP; recent weight loss; recent-onset diabetes; malignant hypertension; pressor response to antihypertensive drugs or during induction of anesthesia; refractory hypertension. Symptoms are usually, but not necessarily, paroxysmal.



Cause Features

Hyperthyroidism Palpitations, tremor, weight loss, sweating, increased appetite.

Primary aldosteronism Unprovoked hypokalemia with inappropriate kaliuresis (24-hr urinary potassium �40 mEq with serum potassium ≤3.5 mEq/L), refractory hypertension

Cushing syndrome Truncal obesity, moon facies, ecchymosis, striae, acne, hirsutism, muscle weakness, osteoporosis, glucose intolerance, hypokalemia

Coarctation of the aorta

Absent, delayed, or diminished arterial pulsations in lower extremities, especially in patients <30 years of age

Medications Birth control pills, amphetamines (diet pills, cold capsules, nasal spray), MAO inhibitors, tricyclic antidepressants, cocaine, adrenal steroids, exogenous thyroid hormone, cyclosporine, erythropoietin

Others Renal parenchymal disease, alcohol >2 oz/d, acromegaly, hypothyroidism, hypercalcemia (hyperparathyroidism), congenital adrenal hyperplasia, pregnancy-induced, neurologic disorders (increased ICP, sleep apnea, quadriplegia, acute porphyria, familial dysautonomia, lead poisoning, Guillain-Barré syndrome), acute stress, systolic hypertension (aortic insuffi ciency, AV fi stula, patent ductus arteriosus, thyrotoxicosis, Paget disease, beriberi, rigidity of aorta)

TREATMENT OF HYPERTENSION

A. Blood Pressure Goals. The goal of BP control is to reduce disability and death associated with hypertension using the least intrusive means. As shown in Table 12.4and Figure 12.2, BP should be reduced to <140/90 mmHg for the general population and to <130/80 mmHg in patients with diabetes or chronic renal disease. It is now known that control of systolic BP, not diastolic BP, is the major risk and goal of therapy. To achieve maximum benefi t, SBP and DBP should be reduced to established targets.

B. Drug Therapy 1. Initial Therapy. The choice of initial drug therapy should be individualized, based on

patient characteristics, associated medical conditions, and BP levels. In general, most patients should be started on a low dose of a long-acting once-daily drug that can be titrated slowly based on the patient’s age and response (e.g., every 1–2 months for Stage 1 hypertension). About 50% of patients respond to monotherapy. In high-risk patients (BP �180/110 mmHg, clinical cardiovascular disease, target organ damage), intervals between adding new drugs and changing existing regimens can be reduced. If BP is >20/10 mmHg above target BP, it is reasonable to initiate therapy with two drugs,

Table 12.3. Causes of Secondary Hypertension (cont'd)



Table 12.4. Initial Treatment of Hypertension

Blood Pressure Classifi cation* Lifestyle Modifi cation Initial Drug Therapy**

Normal (<120 and <80) – –

Prehypertension (120–139 or 80–89) Yes For compelling indication†

Stage 1 (140–159 or 90–99) Yes 1- or 2-drug therapy

Stage 2 (�160/100) Yes 2-drug therapy for most

* When systolic and diastolic pressures fall into different categories, the higher category should be used to classify BP status (e.g., 160/92 mmHg should be classifi ed as stage 2 hypertension). Isolated systolic hypertension is defi ned by an SBP of �140 mmHg with a DBP <90 mmHg and should be staged appropriately (e.g., 170/85 mmHg is defi ned as stage 2 isolated systolic hypertension).

** BP goal <140/90 mmHg. For patients with diabetes or chronic kidney disease, treat to BP <130/80 mmHg. Treat with thiazide diuretic, ACE inhibitor, angiotensin-receptor blocker, beta blocker, calcium antagonist, or combination drug therapy, depending on patient characteristics (e.g., Blacks, elderly), coexistent medical conditions (e.g., diabetes, chronic renal disease), and level of BP. Start 2 drugs in most patients with BP >20/10 mmHg above target BP.† For patients with diabetes mellitus or chronic kidney disease, treat to BP <130/80 mmHg.

Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JAMA 2003;289:2560–2572).

one of which should usually be a thiazide-type diuretic (JAMA 2003;289:2560–2572). Hospitalization should be considered for persons with blood pressures �200/120 mmHg and symptomatic target organ damage. Numerous studies have investigated whether specifi c agents may be benefi cial—or even potentially neuroprotective—for patients who have had a cerebrovascular event; however, data remain inconclusive. The HOPE study (see Chapter 15, Table 15.9) showed lower stroke risk for patients receiving the ACE inhibitor ramipril (compared to placebo) in a cohort that included 11% of patients with prior stroke. But the PROGRESS trial did not fi nd a benefi t for the ACE inhibitor perindopril when given as monotherapy in a population of patients with stroke, TIA, or ICH. However, PROGRESS did fi nd a benefi t for the combination of perindopril with indapamide; these patients achieved greater BP reduction than did patients on ACE inhibitor monotherapy. Most recently, in the PRoFESS study (presented at the 17th European Stroke Conference, Nice, France, May 2008), telmisartan was compared to placebo in more than 20,000 patients with recent stroke. Telmisartan did not signifi cantly prevent stroke in this study.

2. Intensifi cation of Therapy. The sequence for intensifi cation of drug therapy depends on the response to and tolerance of initial therapy. If the initial drug has no effect on BP or causes bothersome side effects, another drug from a different drug class should be substituted. If a partial response is obtained and the drug is well tolerated, a higher dose can be given or a second agent from a different



drug class can be added. (If a diuretic is not chosen as initial therapy, it should probably be added next, as it will enhance the effect of most antihypertensive drugs.) If target BP is still not attained, continue adding drugs from other classes. Before proceeding to each successive treatment step, examine potential reasons for lack of responsiveness, including pseudohypertension (p. 118), nonadherence to therapy, volume overload, drug-related causes, and secondary causes of hypertension. Elevated BP alone in asymptomatic patients without new or worsening target-organ damage rarely requires emergency control.

3. Combination Therapy. Once-daily, fi xed-dose combination therapy, in which a full dose of one drug is replaced by smaller doses of two or more drugs, is a common approach for initial treatment of hypertension. The different mechanisms of action may result in fewer side effects and better BP control, especially in the resistant hypertensive patient. For the 60% of patients and 75% of diabetics who require more than one antihypertensive drug, once-daily, fi xed-dose combination therapy may improve compliance. Useful combinations include a diuretic plus either a beta blocker, calcium antagonist, ACE inhibitor, or angiotensin II receptor blocker; an ACE inhibitor plus a calcium antagonist; an ACE inhibitor plus eplerenone (aldosterone receptor blocker); a diuretic plus an adrenergic blocker plus a vasodilator; or a beta blocker plus a calcium antagonist. Combinations that should be avoided include two drugs from the same class (e.g., two beta blockers); a centrally acting agent and a beta blocker; and a beta blocker plus either diltiazem or verapamil. In the PROGRESS trial, combination therapy with perindopril plus indapamide reduced BP by 12/5 mmHg and recurrent stroke by 43% (p. 162).

4. Stepdown Therapy. Monotherapy ultimately provides adequate BP control for ~50% of patients. Therefore, if BP has been well controlled on two drugs for �6 months, gradual withdrawal of the fi rst drug may be attempted. Close monitoring is advised, as hypertension may return after a delayed period of months to years. Attempts to completely discontinue antihypertensive therapy are generally not recommended without sustained and substantial improvements in lifestyle.

C. Optimizing Patient Compliance. As 50% or more of hypertensive patients adjust or discontinue antihypertensive therapy on their own, education about dietary, lifestyle, and pharmacologic measures is essential. Drugs should be chosen that are affordable, treat coexistent disease, and have convenient dosing and favorable side-effect profi les. Patients should also be educated about the silent nature of the disease and its risks if left untreated. Adherence to antihypertensive therapy can also be improved by challenging patients to play an active role in their disease—recording BP at home, reporting side effects, involving their families, challenging them to reach and maintain the therapeutic goal. Patients should also be encouraged to record and report their BP prior to their morning drug dose (to ensure protection against the surge in BP upon awakening) and in the early evening (to ensure coverage throughout the day). Compliance measures should be reinforced at every visit.



Chapter 13

Control of Dyslipidemia


Elevated plasma levels of total cholesterol and LDL cholesterol, and low plasma levels of HDL cholesterol, are major modifi able lipid risk factors for atherothrombotic vascular disease. It has been estimated that for each 1% decrease in LDL cholesterol and for each 1% increase in HDL cholesterol, the risk for cardiovascular events falls by 2% and 3%, respectively. A meta-analysis of more than 30 trials using diet, drugs (including statins), or surgery to lower cholesterol has shown that for every 1% that total cholesterol is lowered, total mortality is reduced by 1.1% (Circulation 1995;91:2274–2282; Circulation 1998;97:946–952). A meta-analysis of more than 90,000 patients enrolled in randomized trials testing statin drugs found a reduction in stroke risk of 21%, with no heterogeneity of effect among the trials (Stroke 2004;35:2902). The effect was largely driven by reduction in LDL; each 10% reduction in LDL reduced stroke risk by 15.6%. In the Heart Protection Study, 20,536 patients with atherosclerotic arterial disease or diabetes were randomized to simvastatin (40 mg) or placebo. At 5 years, statin therapy reduced the risk of fi rst occurrence of nonfatal or fatal stroke by 25% (4.3% vs. 5.7%, p <0.0001). Cardiac mortality, MI, and revascularization procedures were reduced by 18%, 38%, and 22%, respectively. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study (N Engl J Med 2006;355:549) randomized 4731 patients with recent stroke or TIA (within 6 months) to atorvastatin (80 mg) or placebo. Patients were followed for an average of nearly 5 years. LDL was 129 mg/dL in the placebo group and 73 mg/dL in the treatment group. Stroke risk dropped by 16% among those treated with high-dose atorvastatin, despite the fact that up to 25% of patients in the placebo group were receiving statins outside the trial. The SPARCL investigators also stratifi ed the benefi t by degree of lipid lowering and found that for patients who achieved >50% LDL of their initial LDL, the risk of stroke decreased by 31% (Stroke 2007;38:3198). The level of risk reduction with statins is similar to—or perhaps slightly more than—that achieved with aspirin for patients at high risk of stroke. The benefi cial effects of lipid therapy are due more to plaque stabilization than to changes in stenosis severity, which are generally modest and disproportionate to the 25–80% reduction in major vascular event rates. Plaque stabilization, which can be accomplished in weeks to months with aggressive treatment of dyslipidemia, may be related to resorption of macrophage and extracellular lipid deposits, a decrease in neointimal infl ammation, and maintenance of fi brous cap integrity. Effective treatment transforms the infl amed, friable plaque into a stable, fi brotic plaque that is less prone to ulceration, rupture, and thrombosis. In addition, lipid-lowering therapy improves endothelial dysfunction caused by dyslipidemia, resulting in additional vasodilatory, antithrombotic, and anti-infl ammatory effects. Statins have been shown to have salutary effects in addition to their lipid-lowering capability. They have anti-infl ammatory potential and lower CRP; they have a direct effect on the vascular endothelium, inhibiting absorption of circulating lipids; they may also have neuroprotective capability.

DIAGNOSIS, EVALUATION, AND TREATMENT OF DYSLIPIDEMIA

A. Lipoprotein Analysis. A fasting lipoprotein profi le consisting of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides should be obtained in all adults over age 20 and repeated at least once every 5 years. If a nonfasting test is performed, only total cholesterol and HDL cholesterol measurements are reliable. Blood samples should be drawn after a 9–12-hour fast while the person is in a steady state (absence of active weight loss, acute illness, recent trauma or surgery, pregnancy, or recent change in diet).



B. Exclusion of Secondary Causes. Once a dyslipidemia is identifi ed, a history, physical examination, and basic laboratory tests are performed to screen for secondary causes of dyslipidemia, including diet, medications, alcohol abuse, diabetes, hypothyroidism, nephritic syndrome, chronic renal failure, and obstructive liver disease.

C. Identifi cation of Genetic Dyslipidemia. If severe hypercholesterolemia is present (total cholesterol >300 mg/dL) or a genetic disorder is discovered, a family history and measurement of cholesterol in other family members are needed.

D. LDL and Non-HDL Cholesterol Goals. LDL lowering is the primary goal of therapy for persons with dyslipidemia, and LDL goals vary inversely with CHD risk: individuals at highest risk have the lowest LDL targets. Non-HDL cholesterol (i.e., LDL � VLDL cholesterol, calculated by subtracting HDL cholesterol from total cholesterol) is a secondary goal of therapy after LDL lowering in persons with triglycerides �200 mg/dL. LDL and non-HDL goals are shown in Table 13.1.

E. Metabolic Syndrome. Many persons have a constellation of major and emerging risk factors, referred to as the metabolic syndrome, that increase the risk of coronary and cerebrovascular events at any level of LDL cholesterol. These individuals benefi t from specifi c therapeutic measures beyond LDL lowering. Clinical identifi cation of the metabolic syndrome requires �3 of the following factors: abdominal obesity (waist circumference: men >102 cm [40 in]; women >88 cm [35 in]); triglycerides �150 mg/dL; low HDL cholesterol (men <40 mg/dL; women <50 mg/dL); blood pressure �130/85 mmHg; impaired fasting glucose (fasting glucose 110–125 mg/dL).

Table 13.1. LDL and Non-HDL Cholesterol Goals (Adapted from ATP III Guidelines At-A-Glance, National Institutes of Health, 2004)

Risk Category LDL Goal (mg/dL) Non-HDL Goal* (mg/dL)

CHD or CHD risk equivalent (10-yr risk for CHD >20%†)

<100** <130

�2 risk factors† with 10–yr risk for CHD �20%†

<130 <160

0–1 risk factor‡ <160 <190

CHD risk equivalent = carotid artery disease (TIA or stroke of carotid origin, asymptomatic carotid stenosis >50%), peripheral vascular disease (including abdominal aortic aneurysm), other atherosclerotic vascular disease (e.g., renal artery stenosis), diabetes mellitus, or �2 risk factors conferring 10-year CHD risk >20%.

* To determine non-HDL cholesterol, subtract HDL cholesterol from total cholesterol. Non-HDL cholesterol is a secondary goal of therapy after LDL lowering for persons with triglycerides �200 mg/dL.

** Consider LDL goal <70 for very high risk persons with multiple risk factors (Stroke 2006;37:577).† As determined by the Framingham risk score (Circulation 2002;106:3143–3421).‡ Major risk factors that modify LDL goal include: cigarette smoking, hypertension (BP �140/90 mmHg or on antihypertensive medication), low HDL cholesterol (<40 mg/dL), family history of premature CHD (CHD in male fi rst-degree relative <55 years, CHD in female fi rst-degree relative <65 years), age (men �45 years; women �55 years).

Chapter 13. Control of Dyslipidemia 125


TREATMENT OF ELEVATED LDL CHOLESTEROL

Therapeutic lifestyle changes (diet, physical activity, weight control, smoking cessation) are considered fi rst-line therapy for all patients with dyslipidemia. Drug therapy should be initiated on the initial visit concurrently with lifestyle changes in high-risk persons, including those with prior TIA or stroke or asymptomatic carotid stenosis >50% (Figure 13.1).

TREATMENT OF LOW HDL CHOLESTEROL AND ELEVATED TRIGLYCERIDE

A. Low HDL Cholesterol. HDL is involved in reverse cholesterol transport from the peripheral tissues to the liver. A depressed HDL cholesterol level (<40 mg/dL) is a powerful predictor of vascular risk. Causes of low HDL cholesterol include elevated triglycerides, obesity, physical inactivity, cigarette smoking, very high carbohydrate diets (>60% of calories), type 2 diabetes, drugs (beta blockers, anabolic steroids, progestational agents), and genetic factors. Nonpharmacologic measures that increase HDL cholesterol include weight loss, exercise, and smoking cessation. Diets high in monounsaturated and omega-3 fatty acids can also increase HDL cholesterol without increasing LDL cholesterol. Alcohol increases HDL cholesterol but is not recommended for that purpose. Once LDL and non-HDL goals are achieved, drug therapy to raise HDL cholesterol may be considered for higher-risk individuals (Figure 13.2).

B. Elevated Triglyceride. Elevated triglyceride is an independent risk factor for coronary disease and is associated with atherogenic VLDL remnants and small dense LDL particles, which correlate with the extent and progression of atherosclerosis. ATP III defi nes normal triglyceride as <150 mg/dL, borderline-high triglyceride as 200–499 mg/dL, and very high triglyceride as �500 mg/dL. Since remnant lipoproteins are comprised of partially degraded VLDL particles, elevated VLDL cholesterol levels can be used as a marker for the presence of remnant lipoproteins and elevated risk. ATP III recognizes non-HDL cholesterol (LDL � VLDL cholesterol) as a secondary target of therapy in patients with high triglyceride (�200 mg/dL) and sets the non-HDL goal at 30 mg/dL higher than the LDL goal (Table 13.1), based on the assumption that higher VLDL levels are associated with remnant lipoproteins and increased vascular risk. Non-HDL cholesterol is determined by subtracting HDL cholesterol from total cholesterol. Causes of elevated triglyceride include lifestyle-related causes (obesity, physical inactivity, cigarette smoking, excess alcohol intake, high carbohydrate diet), other secondary causes (diabetes mellitus, chronic renal failure, nephrotic syndrome, Cushing disease, lipodystrophy, pregnancy, various drugs), and genetic causes. The potential benefi ts of lowering triglyceride levels are not as well studied as those of lowering LDL cholesterol. For triglyceride levels of 150–199 mg/dL, emphasis is placed on therapeutic lifestyle changes and LDL lowering; drug therapy to reduce triglycerides is not recommended (Figure 13.3).



TLC ;consider

drug*

Considerdrug1,11

No CHD orCHD risk equivalent

021 risk factor

TLC33 mos. TLC33 mos.

LDL$160

LDL,100 $100

LDL,160 LDL,130

LDL$130

$2 risk factors with10-yr CHD risk,20%

CHD, carotidartery disease,

other CHDrisk equivalent

Elevated LDL Cholesterol

160–189 $190 $130

TLC TLCDrug1 Drug1, ‡

TLC ;plus

drug1

Figure 13.1. Treatment of Elevated LDL Cholesterol

LDL levels are expressed in mg/dL. CHD risk equivalent = carotid artery disease (TIA or stroke of carotid origin; asymptomatic carotid stenosis >50%), abdominal aortic aneurysm, peripheral arterial disease, diabetes mellitus, or multiple (≥2) risk factors with 10-year CHD risk >20%. See footnotes, Table 13.1, for CHD risk factors. TLC = therapeutic lifestyle changes (Chapters 9–14).

* Consider statin therapy, based on results of the Heart Protection Study (p. 166).

+ Initial drug therapy usually consists of moderate dose of a statin. If LDL cholesterol at 6 weeks remains above the LDL target, options include: (1) intensify diet therapy by adding plant sterols/stanols 2 gm/d and increasing soluble fi ber to 10–25 gm/d); (2) intensify statin therapy; (3) consider adding a bile acid sequestrant, niacin, or ezetimibe; (4) if elevated triglyceride or low HDL is present, consider adding nicotinic acid or fi brates to statin therapy; or (5) if LDL is near target, consider maintaining current statin dose. Diffi cult-to-control patients should be referred to a lipid specialist.

++ Especially consider drug therapy for individuals with at least one strong risk factor (severe hypertension, heavy cigarette smoker, family history of premature CHD).

‡ Drug therapy is recommended for persons with a 10-year risk of CHD of 10–20%. If 10-year risk is <10%, drug therapy is optional but may be especially useful in individuals with at least one strong risk factor (severe hypertension, heavy cigarette smoker, strong family history of premature CHD).



For triglyceride levels of 200–499 mg/dL, primary therapy is directed at LDL lowering, and non-HDL cholesterol is a secondary goal of therapy. In addition to weight reduction and increased physical activity, drug therapy may be considered in high-risk patients to achieve the non-HDL cholesterol goal. Pharmacologic approaches include intensifi cation of LDL-lowering therapy, or the addition of nicotinic acid or fi brates when used with appropriate caution. For very high triglyceride levels (�500 mg/dL), the primary goal of therapy is to prevent acute pancreatitis by rapidly lowering triglycerides to <500 mg/dL with very low fat diets (�15% of calories), weight reduction, increased physical activity, and the use of either a fi brate or nicotinic acid. Once triglycerides are <500 mg/dL, attention is directed toward achieving LDL cholesterol and non-HDL cholesterol targets.

DRUG THERAPY FOR DYSLIPIDEMIA

Drug therapy plays a central role in the management of dyslipidemia, improving lipid profi le, slowing the progression of atherosclerosis, stabilizing rupture-prone plaques, reducing the risk of arterial thrombosis, and improving prognosis. For patients who require drug therapy, the drug should be added to, not substituted for, diet therapy and lifestyle modifi cation. Table 13.2 lists effective cholesterol-lowering drugs.

Figure 13.2. Treatment of Low HDL Cholesterol

+Statin is preferred drug therapy.

++For individuals without CHD and one or more risk factors, drug therapy can be considered for higher-risk persons with asymptomatic atherosclerosis by coronary EBCT or arterial neck ultrasound. CHD risk equivalent = carotid artery disease (TIA or stroke of carotid origin; asymptomatic carotid stenosis >50%), abdominal aortic aneurysm, peripheral arterial disease, diabetes mellitus, or multiple (≥2) risk factors with 10-year CHD risk >20%. See footnotes, Table 13.1, for CHD risk factors.

Low HDL Cholesterol

HDL,40 mg/dL HDL $40 mg/dL

No drug therapyunless LDL or

non-HDL is elevated

Achieve LDL goal1 (Figure 13.1)Achieve non-HDL goal (Table 13.1)Consider statin, nicotinic acid, or fibratefor CHD or CHD risk equivalent11



Achieve LDL goal(Figure 13.1)



Elevated Triglyceride (TG)

Borderline high TG(1502199 mg/dL)

High TG(2002499 mg/dL)

Very high TG($599 mg/dL)

Lower TG to ,500 mg/dLto prevent acutepancreatitis:

Other lifestyle changes1

Fibrates3 or nicotinic acid2

Very low fat diet (,15%of total calories) whenTG .1000 mg/dL

Fish oil4

Achieve non-HDL goal*Lifestyle changes first1

Drug therapy11:statins1, nicotinic acid2,fibrates3, fish oil4

Lifestyle changes1

Drug therapy to lowerTG not indicated

Figure 13.3. Treatment of Elevated Triglyceride

+Weight control, increased physical activity, smoking cessation, restriction of alcohol in some, avoidance of high-carbohydrate diets (>60% of total calories), discontinuation of nonessential drugs that raise cholesterol.

++May need high-dose statin or moderate-dose statin plus either nicotinic acid or fi brate.

*See Table 13.1.

1. Statins lower triglycerides by 7–30% (20–50% or higher in patients with severely elevated triglyceride).2. Nicotinic acid lowers triglycerides by 20–50%, but doses ≥2 gm/d can worsen hyperglycemia in persons

with diabetes or insulin resistance.3. Fibrates lower triglycerides by 20–50% but can raise LDL cholesterol in patients with hypertriglyceridemia.

Fibrates are the best choice for acute reductions in triglycerides.4. EPA reduces triglycerides by up to 30% (3 gm/d) or 50% (9 gm/d) and is a useful adjunct to

statin therapy.



Table 13.2. Effective Cholesterol-Lowering Drugs

Drug(usual starting dose/max) Effect on Lipids Comments

HMG-CoA Reductase Inhibitors (Statins)

Atorvastatin (10/80 mg/d)Fluvastatin (20/80 mg/d)Lovastatin (20/80 mg/d)Pravastatin (20/80 mg/d)Rosuvastatin (10/40 mg/d)Simvastatin (20/80 mg/d)

LDL: ↓ 18–55% HDL: ↑ 5–15%

TG: ↓ 7–30%

Major use: Overwhelmingly the drug class of choice for elevated LDL levels. Highly effective for lowering LDL and preventing cardiovascular and cerebrovascular events. Absolute Contraindication (CI): active or chronic liver disease, pregnancy, lactation. Relative CI: concomitant use of cyclosporine, macrolide antibiotics, various antifungal drugs, cytochrome P-450 inhibitors; previous intolerance to statins due to myalgias, elevated liver transaminases, other side effects. Adverse effects: myopathy, ↑ liver transaminases. Fibrates and nicotinic acid should be used with caution in combination.

Nicotinic Acid (Niacin)

Immediate-release form ([1.5–3]/4.5 gm/d) Sustained-release form ([1–2]/2 gm/d) Extended-release form ([1–2]/2 gm/d)

LDL: ↓ 5–25%HDL: ↑ 15–35%

TG: ↓ 20–50%

Major use: Useful in nearly all dyslipidemias. Uniquely effective in atherogenic dyslipidemia. Also useful for elevated Lp(a) levels and as adjunctive therapy for mixed dyslipidemia. Absolute CI: chronic liver disease, severe gout. Relative CI: hyperuricemia, high doses (>3 gm/d) in type 2 diabetes. Caution in active liver or peptic ulcer disease, hyperuricemia, gout. Adverse effects: fl ushing, hyperglycemia, hyperuricemia/gout, upper GI distress, hepatotoxicity (especially sustained-release form).



Table 13.2. Effective Cholesterol-Lowering Drugs (cont'd)

Drug (usual starting dose/max) Effect on Lipids Comments

Bile Acid Sequestrants

Colesevelam ([2.6–3.8]/4.4 gm/d) Cholestyramine ([4–16]/24 gm/d) Colestipol ([5–20]/30 gm/d)

LDL: ↓ 15–30%HDL: ↑ 3–5%TG: usually not affected; may ↑

Major use: Moderate hypercholesterolemia, younger patients with elevated LDL cholesterol, and women with elevated LDL cholesterol who are considering pregnancy (sequestrants are not absorbed out of the Gl tract and lack systemic toxicity). Also useful as adjunctive therapy with statins. Absolute CI: familial dysbetalipoproteinemia, triglyceride >400 mg/dL. Relative CI: triglyceride >200 mg/dL.Adverse effects: GI complaints common, decreased absorption of several drugs.

Fibric Acid Derivatives

Gemfi brozil (600 mg bid)Fenofi brate (160 mg/dL)Clofi brate (1000 mg bid)

LDL: ↑ 5–20% (may ↑ LDL with ↑ baseline TG)HDL: ↑ 10–35%

TG: ↓ 20–50%

Major uses: Hypertriglyceridemia, atherogenic dyslipidemia (especially in type 2 diabetes).Absolute CI: severe hepatic or renal dysfunction, primary biliary cirrhosis, gallbladder disease. Relative CI: combined therapy with statins (occasional occurrence of severe myopathy or rhabdomyolysis). Use with caution when combining with coumarin anticoagulants or cyclosporine. Adverse effects: dyspepsia, upper GI complaints, cholesterol gallstones, myopathy.



Drug (usual starting dose/max) Effect on Lipids Comments

Cholesterol Absorption Inhibitor

Ezetimibe (10 mg/d) LDL: ↓ 18%HDL: ↑ 1%

TG: ↓ 8%

Major use: As an adjunct to statins when further LDL lowering is required. Not recommended in moderate or severe hepatic insuffi ciency. Effectiveness reduced when given within 2–4 hr of bile acid sequestrant. CI: combination with statin in patients with active liver disease or unexplained persistent transaminase elevations.Adverse effects: GI complaints.

↑ = increases, ↓ = decreases, Cl = contraindication, HDL = HDL cholesterol, LDL = LDL cholesterol, Lp(a) = lipoprotein(a), TG = triglyceride.

Table 13.2. Effective Cholesterol-Lowering Drugs (cont'd)



Chapter 14

Other Measures to Prevent Atherothrombosis and Stroke


A. Control of Diabetes Mellitus. Diabetes mellitus is associated with a 1.5–3-fold increased risk of stroke. Tight control of blood glucose is associated with a reduction in microvascular disease—neuropathy, retinopathy, nephropathy—although the impact of intensive glycemic control on macrovascular complications including coronary artery disease and cerebrovascular disease is less well established. Nevertheless, normalization of blood glucose levels through diet, exercise, oral hypoglycemic agents, and insulin is recommended for overall vascular health.

B. ACE Inhibitors. ACE inhibitors have been shown to improve prognosis in a wide variety of vascular disorders, including hypertension, heart failure, asymptomatic LV dysfunction, MI, stroke, post-coronary revascularization procedures, and proteinuric nephropathy. In the HOPE trial, 9297 patients with either atherosclerotic arterial disease (prior MI, prior stroke, or peripheral arterial disease) or diabetes plus one additional risk factor (hypertension, elevated total cholesterol, depressed HDL cholesterol, smoking, or microalbuminuria) were randomized to ramipril (10 mg/d) or placebo. At a mean follow-up of 5 years, ramipril reduced the primary composite endpoint of MI, stroke, or death from cardiovascular disease by 22% (14.0% vs. 17.8%, p <0.001). Signifi cant risk reduction was also noted for individual endpoints of MI (20%), stroke (32%), cardiac arrest (38%), revascularization procedures (15%), and new-onset diabetes mellitus (34%) (N Engl J Med 2000;342:145–153). The benefi cial effects of ramipril were observed in patients with and without diabetes, hypertension, or cardiovascular disease and were independent of the effects of concomitant cardiovascular medications (aspirin, beta blockers, lipid-lowering agents, other BP drugs). In a substudy of HOPE, long-term treatment with ramipril had benefi cial effects on atherosclerosis progression, as assessed by B-mode carotid ultrasound (SECURE trial; Circulation 2001;103:919–925). The recommended starting dose of ramipril to reduce the risk of MI, stroke, and death from cardiovascular causes in patients 55 years or older at high risk of developing a major cardiovascular event is 2.5 mg once daily for 1 week, followed by 5 mg once daily for the next 3 weeks, then increased as tolerated to a maintenance dose of 10 mg once daily (which may be given in two divided doses for hypertensive or recent post-MI patients). ACE inhibitors are generally safe, well tolerated, and affordable. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), 6105 patients with prior TIA or stroke with or without hypertension were randomly assigned active treatment (perindopril [4 mg/d] ± the diuretic indapamide at the discretion of treating physician) vs. placebo. At 4-year follow-up, active treatment resulted in a 28% relative reduction in recurrent stroke (10% vs. 14%, p <0.0001) and a relative reduction in total major vascular events by 26%. Stroke was reduced to similar degrees in hypertensive and non-hypertensive subgroups. In patients receiving combination therapy with perindopril plus indapamide, BP was reduced by 12/5 mmHg, and stroke risk, by 43%; single-drug therapy reduced BP by 5/3 mmHg but did not reduce the risk of stroke. Patients with atherothrombotic vascular disease or diabetes should be considered for ACE inhibitor therapy unless they have an intolerable cough, SBP consistently below 100–110 mmHg, or renal failure (creatinine >2.5 mg/dL).



C. Low-Dose Fish Oil. In the GISSI Prevention Study of 11,324 patients with prior MI, 1 gm/d (850 mg of DHA and EPA) of fi sh oil, a dose too low to affect lipid levels, reduced total mortality by 20% at 3.5 years, due in large part to a 45% reduction in sudden cardiac death (Lancet 1999;354:447–455)(p. 165). Similar clinical benefi ts were seen in DART, in which men with prior MI who were instructed to eat fatty fi sh at least twice weekly had a 29% reduction in total mortality (Lancet 1989;2:757–761). Consumption of fi sh and omega-3 fatty acids has also been shown to reduce the risk of stroke or CHD in healthy persons and is an important component of the Mediterranean-style diet (Chapter 10).

D. Arterial Revascularization 1. Carotid endarterectomy. CEA is indicated for reducing the risk of ipsilateral

hemispheric stroke in patients with asymptomatic carotid artery stenosis >60% who do not have severe comorbidities when operated on by surgeons with morbidity and mortality records <3%. The Asymptomatic Carotid Artery Stenosis (ACAS) trial showed >50% reduction in stroke at 5 years for endarterectomy compared to aspirin (11% vs. 5.1%) (JAMA 1995;273:1421); this effect was seen in men but not in women in ACAS. It has been estimated that 83 patients with asymptomatic carotid artery stenosis would have to undergo CEA in order to prevent one stroke at 2 years. The MRC Asymptomatic Carotid Surgery Trial (ACST) (Lancet 2004;363:1491) found a benefi t to surgery similar to that seen in ACAS. While this study did fi nd a benefi t for women, it was smaller than that seen in men; patients >65 years old also fared less well. CEA is also indicated for reducing the risk of recurrent ischemic stroke in symptomatic patients with moderate-to-high grade stenosis (>50–69%) of the ICA. The number of treated patients needed to prevent one stroke at 2 years is 8 for stenosis severity of 70–99% and 20 for stenosis severity of 50–69%. Patients should begin antiplatelet therapy with aspirin before surgery.

2. Angioplasty and stenting. Small series report angiographic success rates >90%, with complication rates ranging from 0–20% for carotid artery stenting. Distal microembolization protection devices, potent antithrombotic and antiplatelet drug regimens, and increased operator experience are likely to further improve procedural outcome. In the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), there was no difference between endovascular treatment (stent/balloon angioplasty) and CEA with respect to major events at 30 days or ipsilateral ischemic stroke at 3 years (Lancet 2001;357:1729–1737). In the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, carotid stenting with distal embolic protection was compared to CEA in patients with >50% symptomatic stenosis or >80% asymptomatic stenosis. Stenting with distal embolic protection reduced the 30-day combined endpoint of death, MI, or stroke by 39% compared to CEA. While SAPPHIRE was a noninferiority trial, stenting achieved near-superiority compared with CEA for the primary endpoint (p � 0.053) (N Engl J Med 2004;351:1493–1501). The Stent-Protected Angioplasty versus Carotid Endarterectomy in symptomatic patients (SPACE) trial (Lancet 2006;368:1239–1247)

Chapter 14. Other Measures to Prevent Atherothrombosis and Stroke 135


randomized 1183 patients with symptomatic stenosis of >50% to carotid surgery or stenting. The choice of the stenting device and other methodology, including the use of distal protection device, was left to the interventionalist. Protection devices were used in only 27% of patients, and no signifi cant difference in the rate of death or ipsilateral stroke was seen at 30 days between the treatment arms. The Endarterectomy Versus Angioplasty in patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial (N Engl J Med 2006;355:1660–1671) found that stented patients did worse than patients treated with endarterectomy. The Stenting of Symptomatic Atherosclerostic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA) trial (Stroke 2004;35:1388–1392) was a non-randomized prospective study that enrolled 61 patients and used the Neurolink intracranial stent system. Of these, 43 had intracranial stenosis and 18 had extracranial vertebral artery stenosis. In SSYLVIA, stenting was associated with a 6.6% stroke rate at 30 days, and stents were successfully placed in 58/61 patients. The Wingspan is another intracranial stent, which combines balloon angioplasty with placement of a self-expanding nitinol microstent. In a prospective study of 45 patients with symptomatic intracranial atherosclerosis, revascularization was achieved in 98%, with a 30-day stroke rate of 4.5% (Neuroradiology 2005;47:222–228).

E. Folic Acid. Homocysteine is an amino acid by-product of protein metabolism. Although the mechanism of action is not clearly understood, homocysteine appears capable of damaging endothelium and promoting a prothrombogenic environment, and an elevated fasting homocysteine level is an independent risk factor for vascular events, particularly in patients already diagnosed with atherothrombotic vascular disease. However, the Vitamin Intervention for Stroke Prevention (VISP) trial (JAMA 2004;291:565–575) did not show a benefi t to high-dose vitamin supplementation (a combination of pyridoxine, cobalamin, and folate) over low dose. The risk of all vascular endpoints was the same at 2 years. A second, similar study (Vitamins to Prevent Stroke: VITATOPS) with more patients has not yet reported results. Nonetheless, it is reasonable to encourage all adults to take at least 400 mcg of folic acid daily by diet and/or supplementation, which will lower homocysteine levels. Foods that are rich in folate include broccoli, spinach, other green leafy vegetables, citrus fruits, asparagus, and beans. Currently there are no consensus panel recommendations on criteria for measurement of homocysteine. In our practices, we measure homocysteine in patients with premature or severe atherosclerosis. Folic acid supplementation as well as supplementation with vitamins B

6 and B

12 have been shown

to decrease homocysteine levels by approximately 15–30%. If elevated homocysteine levels are present, folic acid (800–2000 mcg/d), vitamin B

12 (250 mcg/d), and vitamin B

6

(20–25 mg/d) should be prescribed.

F. Antioxidants. Because oxidation of LDL cholesterol is required for LDL to accumulate into evolving atherosclerotic plaque and to stimulate neointimal infl ammation, attention has focused on the use of antioxidant vitamins for primary and secondary prevention of atherosclerosis. At present, no clear evidence shows that use of vitamin E, vitamin C, or beta-carotene reduces atherosclerotic events.



G. Hormone Replacement Therapy. Two Women’s Health Initiative Studies (involving more than 160,000 postmenopausal women) were stopped prematurely because of adverse outcomes. The combined hormone replacement therapy arm of the WHI was stopped in May 2002 after a mean of 5.2 years’ follow-up, because of an excess of breast cancer among treated women (JAMA 2002;288:321–333). The risks of CHD, stroke, and pulmonary embolism were signifi cantly increased in the intervention group; however, hip fracture and colorectal cancer frequency were reduced, and there was no difference in mortality risk. The estrogen-alone arm of the WHI study was stopped in February 2004, due to excess stroke risk (JAMA 2004;291:1701–1712). These results indicate that hormone replacement therapy should not be initiated or continued for primary or secondary prevention of atherothrombotic vascular disease. Raloxifene, a selective estrogen receptor modulator (SERM) has been studied for the prevention of vascular events in postmenopausal women. In the Raloxifene Use for The Heart (RUTH) Study (N Engl J Med 2006;355:125–137), 10,101 postmenopausal women with heart disease or multiple risk factors for heart disease were randomized to 60 mg of raloxifene daily or placebo and followed for a median of 5.6 years. Although no reduction in vascular-event risk (MI, death from coronary causes, or hospitalization for acute coronary syndrome) was reported, a 44% reduction in invasive breast cancer rates and a reduced frequency of vertebral fractures were reported.

H. Citicoline. Citicoline (cytidine-5-diphosphocholine) is an intermediary in the biosynthesis of the membrane phospholipid phosphatidylcholine. Because phospholipids are essential components of cell membranes, agents that promote their generation are a promising strategy in neuroprotection and recovery after brain injury, including ischemic and hemorrhagic stroke. In the immediate post-stroke period, citicoline may act to aid in repair of neuronal membranes and reduce generation of free fatty acids, which limits free radical formation. Over a longer period, increased phospholipid availability may promote neurogenesis, axonal sprouting, and synaptogenesis. Clinical trials of citicoline have involved more than 11,000 patients, but the largest trials have failed to fi nd a positive outcome on their primary endpoints (see Chapter 15). However, a meta-analysis (Stroke 2002;33:2850–2857) assessing outcome for patients with moderate-to-severe stroke treated within 24 hours found that citicoline-treated patients had an improved chance of recovery (25.2% vs. 20.2% for placebo; OR, 1.33; p = 0.0034). In the meta-analysis, patients receiving the highest citicoline dose (2000 mg/d) had the best outcome (27.9% recovered; p = 0.0043). A new randomized trial of high-dose citicoline given within 24 hours of moderate-to-severe ischemic stroke (the ICTUS study) has been enrolling patients since 2006. Citicoline is also being studied in ICH, where small trials have shown modest benefi t. Citicoline has a good safety profi le, with no major safety concerns found in the clinical trials. It is available by prescription in more than 50 countries (including Spain and France). In the US, it is sold as a dietary supplement available without a prescription.

Chapter 14. Other Measures to Prevent Atherothrombosis and Stroke 137


SECTION 3

CLINICAL TRIALS

Chapter 15. Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .141


Chapter 15

Clinical Trials


Table 15.1. Stroke Prophylaxis in Atrial Fibrillation

Trial Design Results

ACTIVE A: Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-Aspirin (N Engl J Med published online March 31, 2009)

7554 patients with AF who had an increased risk of stroke and for whom warfarin was unsuitable, randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin (75–100 mg/d).

Patients treated with clopidogrel plus aspirin had a major vascular event rate of 6.8%/year (vs. 7.6%/ year), an 11% risk reduction (p = 0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel (2.4%/year vs. 3.3%/year; RRR, 28%; p <0.001). Major bleeding was more likely in patients receiving the combination (2.0%/year vs. 1.3%/year; p <0.001).

ACTIVE W: Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events–Warfarin (Lancet 2006;367:1903–1912)

6706 patients with AF plus ³1 risk factors for stroke, randomly allocated to receive warfarin (target INR, 2.0–3.0) or clopidogrel (75 mg/d) plus aspirin (75–100 mg/d).

The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. Clopidogrel/aspirin patients had an annual event rate of 5.6%, vs. 3.93% on oral anticoagulation (p = 0.0003).

AFASAK: Copenhagen Atrial Fibrillation Aspirin Anticoagulation Study (Lancet 1989;1:175)

1007 patients (mean age, 73) with AF were randomized to warfarin (INR, 2.8–4.2), aspirin (75 mg/d), or placebo.

Annual rate of thromboembolism (stroke, TIA, systemic embolism): 2% in warfarin group vs. 5.5% in aspirin and placebo groups.

BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation (N Engl J Med 1990;323:1505)

628 patients (mean age, 68) with AF were randomized to warfarin (INR, 1.5–2.7) vs. other medical therapy.

Annual rate of stroke: 0.4% in warfarin group vs. 3% in control group. No benefi t for aspirin.




EAFT: European Atrial Fibrillation Trial (Lancet 1993;342:1255)

1007 patients; mean age, 73. Warfarin-eligible patients were randomized to warfarin (INR, 2.5–4), aspirin (300 mg/d), or placebo. Warfarin-ineligible patients were randomized to aspirin or placebo.

Annual rate of stroke: 8% in warfarin group vs. 15% in aspirin group vs. 19% in placebo group. Annual rate of major bleeding: 2.8% in warfarin group vs. 0.9% in aspirin group.

SPAF: Stroke Prevention in Atrial Fibrillation Study (Circulation 1991;84:527;Lancet 1994;343:687; Lancet 1996;348:633)

1330 patients; mean age, 67. Warfarin-eligible patients were randomized to warfarin (INR, 2–3.5), aspirin (325 mg/d), or placebo. Warfarin-ineligible patients were randomized to aspirin or placebo.

Annual rate of stroke: 2.3% in warfarin group vs. 7.4% in placebo group. Annual rate of stroke in warfarin-ineligible patients: 3.6% in aspirin group vs. 6.3% in placebo group. Annual rate of major bleeding: 1.5% in warfarin group vs. 1.4% in aspirin group vs. 1.6% placebo group.

SPAF II: Stroke Prevention in Atrial Fibrillation (Lancet 1994;343:687)

1100 patients (mean age, 69) with AF were randomized to warfarin (INR, 2–4.5) vs. aspirin (325 mg/d).

Age <75: Ischemic stroke and systemic embolism: 1.3%/year in warfarin group vs. 1.9%/year in aspirin group. Major hemorrhage: 0.9%/year in aspirin group vs. 1.7%/year in warfarin group.Age >75: Ischemic stroke and systemic embolism: 3.6%/year in warfarin group vs. 4.8%/year in aspirin group. Major hemorrhage: 4.2% in warfarin group (71% of ICHs were fatal) vs. 1.6% in aspirin group.

Table 15.1. Stroke Prophylaxis in Atrial Fibrillation (AF) (cont'd)

Chapter 15. Clinical Trials 143


Table 15.1. Stroke Prophylaxis in Atrial Fibrillation (AF) (cont'd)


SPAF III: Stroke Prevention in Atrial Fibrillation III (Lancet 1996;348:633; JAMA 1998;279:1273)

1044 patients (mean age, 72) with AF and ³1 risk factors were randomized to low-intensity fi xed-dose warfarin (INR, 1.2–1.5) plus aspirin (325 mg/d) vs. adjusted-dose warfarin (target INR, 2.4).892 patients at “low risk” of thromboembolism (no recent CHF, previous embolism, SBP >160 mmHg, or females > age 75) treated with aspirin (325 mg/d).

Ischemic stroke or systemic embolism: 7.9%/year in fi xed-dose warfarin plus aspirin group vs. 1.9%/year in adjusted-dose warfarin group. In “low-risk” AF patients treated with aspirin alone, the rates of ischemic stroke (2%/year) and disabling ischemic stroke (0.8%/year) were low. The rate of major bleeding was 0.5%/year.

SPORTIF-III: Stroke Prophylaxis Using an Oral Thrombin Inhibitor in Atrial Fibrillation (Lancet 2003;362:1691–1698)

3407 patients with nonvalvular AF and ≥1 additional risk factor for stroke (previous stroke, hypertension, heart failure) were randomized (open-label) to ximelagatran (36 mg bid) or warfarin (INR, 2–3). Follow-up: 17 months.

Similar rates of stroke and systemic embolic events between groups. Lower combined annual rate of primary events, major bleeding, and death with ximelagatran (4.6% vs. 6.1%; p = 0.022).

SPORTIF-V Stroke Prophylaxis Using an Oral Thrombin Inhibitor in Atrial Fibrillation (JAMA 2005;293:690–698)

3922 patients with nonvalvular AF and additional stroke risk factors randomized (blinded) to adjusted-dose warfarin (INR goal, 2.0–3.0) or fi xed-dose oral ximelagatran (36 mg bid).

The primary endpoint was noninferiority of ximelagatran vs. warfarin. The annual event rate was 1.2% for warfarin-treated patients, 1.6% for ximelagatran-treated patients (p value for noninferiority, <0.001). Serum ALT levels rose to >3 times the upper limit of normal in 6% of patients treated with ximelagatran. One case of documented fatal liver disease and one other suggestive case occurred.



Table 15.2. Antiplatelet Therapy for TIAs or Minor Strokes


AAASPS: African American Antiplatelet Stroke Prevention Study (JAMA 2003;289:2947)

1809 black men and women with recent noncardioembolic stroke were randomized to aspirin (650 mg/d) or ticlopidine (250 mg bid).

No difference in combined endpoint of recurrent stroke, MI, or vascular death at 6.5 years. Trend toward fewer strokes with aspirin (p = 0.8). Serious neutropenia occurred in 3.4% of ticlopidine group.

AAT: American Aspirin Trial (Stroke 1977;8:301)

178 patients with carotid-territory TIAs (66% men) were randomized to aspirin (1300 mg/d) vs. placebo.

Aspirin benefi t for combined endpoint of mortality + brain +retinal infarcts, but no difference in individual events.

AICLA: Trial Accidents Ischémiques Cérébraux Liés Athérosclérose (Stroke 1983;14:5)

604 patients with small strokes (84%) or TIAs were randomized to aspirin (1000 mg/d) vs. aspirin plus dipyridamole (225 mg/d) vs. placebo × 3 years.

42% risk reduction in stroke for patients on aspirin vs. placebo. No added benefi t for dipyridamole.

American-Canadian Cooperative Stroke Study (Stroke 1985;16:406)

890 patients (67% men) with carotid-territory TIAs were randomized to aspirin (1300 mg/d) vs. aspirin plus dipyridamole (225 mg/d).

No difference in outcome. No added benefi t for dipyridamole.

Canadian Cooperative Study Group (N Engl J Med 1978; 299:53)

585 patients (69% men) with threatened stroke were randomized to aspirin (1300 mg/d), sulfi npyrazone, aspirin plus sulfi npyrazone, or placebo.

Aspirin reduced the rate of stroke and death by 31% (p <0.05). Risk reduction was 48% in men, but no signifi cant reduction in women. No benefi cial effect for sulfi npyrazone.

CAPRIE See p. 164. See p. 164.

CATS: Canadian-American Ticlopidine Study (Lancet 1989;3:1215)

1053 patients with stroke were randomized to ticlopidine (500 mg/d) vs. placebo.

Risk reduction with ticlopidine for the primary combined endpoint (nonfatal MI, vascular death, recurrent stroke) was 23% (intention-to-treat analysis) and 30% (actual-treatment analysis). Benefi t for men and women.



Table 15.2. Antiplatelet Therapy for TIAs or Minor Strokes (cont'd)


Dutch TIA trial (N Engl J Med 1991;325:1261)

3131 patients with TIAs (33%) or minor strokes were randomized to carbaspirin calcium (30 mg/d) vs. (283 mg/d).

No difference in TIA or stroke between two aspirin doses. Lower doses with less GI effects.

ESPS: European Stroke Prevention Study (Lancet 1987;2:1351)

2500 patients with strokes (60%) or TIAs were randomized to aspirin (975 mg/d) plus dipyridamole (225 mg/d) vs. placebo.

Active treatment with aspirin and dipyridamole reduced the risk of stroke and death by 33%.

ESPS-2: European Stroke Prevention Study 2 (J Neurol Sci 1996;143:1)

6602 patients with stroke or TIA were randomized to aspirin (25 mg bid), extended-release dipyridamole (200 mg bid), both, or placebo � 2 years.

Stroke reduction compared to placebo: aspirin (18%), dipyridamole (16%), aspirin plus dipyridamole (37%). Compared to aspirin, the combination of aspirin and extended-release dipyridamole reduced stroke by 23%.

MATCH: Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (Lancet 2004;364:331–337)

7599 high-risk patients with recent ischemic stroke orTIA and at least one additional vascular risk factor randomized to clopidogrel (75 mg/d) or clopidogrel (75 mg/d) plus aspirin (75 mg/d).

For the primary outcome—a composite of ischemic stroke, MI, vascular death, orrehospitalization for acute ischemia (including rehospitalization for TIA, angina pectoris, or worsening of peripheral arterial disease)—there was a nonsignifi cant difference between the two treatment groups (15.7% for combination therapy, 16.7% for clopidogrel monotherapy). Life-threatening bleeds were higher in the group receiving aspirin and clopidogrel versus clopidogrel alone (2.6% vs. 1.3%), with absolute risk increase of 1.3% (95% CI, 0.6–1.9). Major bleeds were also increased in the group receiving aspirin and clopidogrel.




PICSS: PFO In Cryptogenic Stroke Study (Circulation 2002;105:2625–2631)

A substudy of WARSS (p. 148); a 42-center study that evaluated TEE fi ndings in 630 patients randomly assigned to warfarin or aspirin.

PFO was present in 33.8% of patients; the presence of a PFO did not increase stroke risk; no benefi t for patients with PFO to warfarin over aspirin; neither the size of the PFO nor the presence of a concomitant ASD increased stroke risk or modifi ed response to warfarin vs.aspirin.

PRoFESS: Prevention Regimen For Effectively Avoiding Second Strokes (antiplatelet results: N Engl J Med 2008;359:1238–1251; telmisartan results: XVII European Stroke Conference (ESC), May, 2008, Nice, France)

20,332 patients randomized to aspirin (25 mg) and dipyridamole (200 mg/bid), or clopidogrel (75 mg); study began with clopidogrel plus aspirin (75 mg), but protocol changed after release of MATCH results; in a 2 � 2 factorial design, patients were also randomized to telmisartan (80 mg) or placebo.

In 2.5 years of follow-up, recurrent stroke occurred in 9.0% of patients receiving aspirin/extended-release dipyridamole combination and in 8.8% of those receiving clopidogrel (NS). Overall, patients randomized to telmisartan had no benefi t in terms of stroke prevention (8.7% for telmisartan vs. 9.2% for placebo; p = 0.23). However, beyond 6 months from the start of the trial, telmisartan signifi cantly reduced the number of secondary strokes (5.3% vs. 6.0%; p = 0.029).

SALT: Swedish Aspirin Low-Dose Trial (Lancet 1991; 338:1345)

1360 patients with TIA or minor stroke were randomized to aspirin (75 mg/d) vs. placebo.

Low-dose aspirin reduced the risk of stroke or death by 18% vs. placebo.





TASS: Ticlopidine Aspirin Stroke Study (N Engl J Med 1989;321:501)

3069 patients with TIA or minor stroke were randomized to ticlopidine (500 mg/d) vs. aspirin (1300 mg/d).

Ticlopidine reduced the risk of stroke at 3 years by 21% (10% vs. 13%, p = 0.024) and the risk of stroke or death by 12% (17% vs. 19%, p = 0.048). Neutropenia was more common with ticlopidine.

UK-TIA: United Kingdom TIA Aspirin Trial (J Neurol Neurosurg Psychiatry 1991;54:1044)

2435 patients (73% men) with TIAs were randomized to aspirin (1200 mg/d) vs. aspirin (300 mg/d) vs. placebo � 4 years.

Aspirin (both doses combined) reduced the risk of the combined endpoint (MI, stroke, death) compared to placebo. No signifi cant difference between aspirin doses, but event rate was low.

WARSS: Warfarin-Aspirin Recurrent Stroke Study (N Engl J Med 2001;345:1444–1451)

2206 patients with prior noncardioembolic ischemic stroke were randomized to warfarin (INR, 1.4–2.8) or aspirin (325 mg/d). Primary endpoint: recurrent ischemic stroke or death from any cause at 2 years.

No difference between groups with respect to the primary endpoint (warfarin 17.8% vs. aspirin 16%) or the rate of major hemorrhage.

WASID-R: Warfarin-Aspirin Symptomatic Intracranial Disease Study Retrospective (Neurology 1995;45:1488)

Retrospective, multicenter trial of 151 patients (88 warfarin; 63 aspirin) with 50–99% stenosis of an intracranial artery (carotid, MCA, ACA, PCA, vertebral, or basilar) by angiography and a TIA or stroke in that territory.

Warfarin reduced the risk of recurrent vascular events by 50% at 14 months.





WASID-Prospective Warfarin- Aspirin Symptomatic Intracranial Disease Study Prospective (N Engl J Med 2005;352(13):1305–1316)

Patients with TIA or stroke caused by angiographically verifi ed 50–99% stenosis of a major intracranial artery randomized to receive warfarin (target INR, 2.0– 3.0) or aspirin (1300 mg/d).

Study stopped after 569 patients enrolled due to increased adverse events in warfarin arm. During a mean follow-up period of 1.8 years, death occurred in 9.7% of patients treated with warfarin (vs. 4.3% in aspirin-treated group, p = 0.02). Major hemorrhage occurred in 8.3% (warfarin) vs. 3.2% (aspirin) (p = 0.01). The primary endpoint occurred in 22.1% of patients in aspirin group and 21.8% of those in warfarin group (NS).

Table 15.3. Antiplatelet/Antithrombotic Therapy for Acute Stroke


Abciximab in Acute Ischemic Stroke (Stroke 2000;31:601–609)

74 patients with ischemic stroke <24 hr were randomized to dose-escalating abciximab or placebo.

There were no cases of major ICH on CT at 24–36 hr. Asymptomatic parenchymal hemorrhage was detected in 7% of abciximab patients vs. 5% in the placebo group. At 3 months, there was a trend toward less residual disability with abciximab.

AbESST: Abciximab in Emergent Stroke Treatment Trial (Stroke 2005;36:880–890)

400 patients with ischemic stroke <6 hr and NIHSS score of 4–22 were randomized to abciximab (0.25 mg/kg IV bolus plus 0.125 mcg/kg/min infusion � 12 hr) or placebo.

Symptomatic ICH through discharge or day 5 (if earlier): abciximab 3.6% vs. placebo 1.1%. Results at 3 months (abciximab vs. placebo): MRS score of 0 (23.5% vs. 13.5%); MRS score of 1 (25% vs. 26.5%); death (9% vs. 12.5%).





AbESST II: Abciximab in Emergent Stroke Treatment Trial (Stroke 2008;39:87–99)

1800 patients planned; study terminated after 808. Two study cohorts: 0–5 hr after stroke onset, and 5–6 hr OR patient able to be treated within 3 hr of waking up with symptoms. Patients randomized to IV abciximab or placebo.

Within 5 days of enrollment, 5.5% of abciximab-treated and 0.5% of placebo-treated patients in the primary cohort had symptomatic or fatal ICH (p = 0.002). Although the number of patients was small, an increased rate of hemorrhage was noted within 5 days among patients in the wake-up population who received abciximab (13.6% vs. 5% for placebo). At 3 months, 32–33% of patients in both treatment groups had favorable outcome.

CAST: Chinese Acute Stroke Trial (Lancet 1997;349:1641)

21,106 patients within 48 hr of acute ischemic stroke were randomized to aspirin (160 mg/d) vs. placebo for up to 4 weeks.

Small but signifi cant benefi ts for aspirin in terms of early mortality (3.3% vs. 3.9%) and recurrent ischemic stroke (1.6% vs. 2.1%). Brain imaging was suboptimal.

HAEST: Heparin in Acute Embolic Stroke Trial (Lancet 2000;335:1205)

449 patients with acute ischemic stroke within 30 days and AF were randomized to dalteparin (100 IU/kg SQ bid) vs. aspirin (160 mg/d).

No difference in recurrent ischemic stroke or hemorrhage rates between groups at 14 days.

Intravenous Heparin within the First 3 Hours after Onset of Symptoms as a Treatment for Acute Nonlacunar Hemispheric Cerebral Infarctions (Stroke 2005;36:2415–2420).

418 patients with signs of nonlacunar cerebral infarction, randomized within 3 hr of symptom onset to heparin with a PTT goal of 2–2.5 times control, or placebo.

Greater proportion of heparin-treated patients independent (38.9% vs. 28.6%; p = 0.025). However, there were more brain hemorrhages (6.2% vs. 1.4%; p = 0.008).

Table 15.3. Antiplatelet/Antithrombotic Therapy for Acute Stroke (cont'd)




IST: International Stroke Trial (Lancet 1997;349:1569)

19,435 patients with acute ischemic stroke were randomized to aspirin (300 mg/d), subcutaneous heparin (5000 units bid or 12,500 units bid), aspirin plus heparin, or neither.

Aspirin-treated patients had slightly fewer deaths at 14 days (9.0 vs. 9.4%), signifi cantly fewer recurrent ischemic strokes at 14 days (2.8% vs. 3.9%), and no excess of hemorrhagic strokes (0.9% vs. 0.8%). Patients receiving heparin had fewer deaths or recurrent strokes; however, there were more hemorrhagic strokes and serious extracranial hemorrhage, mostly in the higher-dose heparin group, resulting in no net benefi t for heparin. Anticoagulant monitoring and brain imaging were suboptimal.

Low-molecular-weight Heparin for Stroke (nadroparin) (N Engl J Med 1995;333:1588)

312 patients with acute ischemic stroke were random ized to placebo, low-dose nadroparin (4100 U/d), or high-dose nadroparin (4100 U bid).

Dose-dependent reduction in death and dependence at 6 months with nadroparin.

Oral Aspirin vs. Intravenous Heparin for Acute Ischemic Stroke Progression (JNS 2001;187[suppl 1]:S258)

113 patients with ischemic stroke <48 hr were randomized to IV heparin � 6 days followed by aspirin or to aspirin alone (300 mg/d).

No difference in worsening in NIHSS score by ≥1 point at 1 week (aspirin 12.8% vs. heparin 13.3%).

STAT: Stroke Treatment with Ancrod Trial (JAMA 2000;283:2395)

500 patients within 3 hr of acute ischemic stroke were randomized to ancrod (difi brinogenating agent) vs. placebo.

More patients with favorable functional status in ancrod group (42% vs. 34%); mortality similar but trend toward more ICH with ancrod.





TOAST: Trial of Org 10172 in Acute Ischemic Stroke (JAMA 1998;279:1304)

1281 patients with acute ischemic stroke <24 hr were randomized to IV Org 10172 (danaparoid) vs. placebo � 7 days.

More patients with “very favorable” functional outcomes at 7 days received Org 10172; these differences were not sustained at 3 months. Increased risk of ICH in Org 10172 group.

Table 15.4. Randomized Thrombolysis Trials


ASK: Australian Streptokinase Trial (JAMA 1996;276:961)

340 patients with acute ischemic stroke <4 hr were randomized to streptokinase (SK; 1.5 million units IV) or placebo.

Trend toward favorable outcome (combined death and disability score) at 3 months in patients treated with SK within 3 hr of symptom onset, but trend toward poor outcome in patients receiving SK >3 hr.

Association of Outcome with Early Stroke Treatment: Pooled Analysis of ATLANTIS, ECASS, and NINDS rt-PA Stroke Trials (Lancet 2004;363:768–774)

Pooled data from six randomized placebo-controlled trials of IV tPA, with a total of 2775 patients. Using multivariable logistic regression the relation between the interval from stroke onset to start of treatment and favorable 3-month outcome and on the occurrence of clinically relevant parenchymal hemorrhage was assessed.

Odds ratio of a favorable 3-month outcome increased as onset to treatment time decreased (p = 0.005). There was a statistically positive benefi t to 4.5 hr.Onset to Treatment OR for Good

Time Outcome 0–90 min 2.8 91–180 min 1.6 181–270 min 1.4 271–360 min 1.2 Hemorrhage was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p <0.0001). Hemorrhage risk was not associated with onset-to-treatment time but was associated with increased age.





ATLANTIS: Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (JAMA 1999;282:2019)

613 patients with acute ischemic stroke within 3–5 hr were randomized to tPA or placebo.

No signifi cant difference in functional recovery at 90 days between groups. Risk of symptomatic ICH was increased with tPA.

DIAS-2: Desmoteplase in Acute Ischemic Stroke (Lancet Neurology 2009;8(2):141–150)

193 patients randomized (1:1:1) to desmoteplase 125 mcg/kg, desmoteplase 90 mg/kg, or placebo, treated within 3–9 hr after stroke. Patients had “tissue at risk” identifi ed by MRI or CT.

30% of patients had visible occlusion at presentation. Clinical response rates were 47% for 90 mcg/kg dose, 36% for 125 mcg/kg dose, and 46% for placebo. Hemorrhage rates were low (3.5% for 90 mcg/kg, 4.5% for 125 mcg/kg, and 0% for placebo). Mortality was increased in the high-dose group (21% vs. 11% for 90 mcg/kg and 6% for placebo).

ECASS:European-Australasian Cooperative Acute Stroke Study (JAMA 1995;274:1017)

620 patients with acute ischemic stroke <6 hr were randomized to 1.1 mg/kg tPA or placebo.

No difference in disability using intention-to-treat analysis. However, there were 109 major protocol violations (including concomitant use of heparin). Post hoc analysis excluding these patients indicated better recovery for tPA group at 90 days.

ECASS II: European-Australasian Cooperative Acute Stroke Study II (Lancet 1998;3529136:1245–1251)

800 patients with acute ischemic stroke <6 hr randomized to 0.9 mg/kg tPA or placebo.

Nonsignifi cant trend to more favorable disability outcomes in treated patients; post hoc analysis found an absolute reduction of death and dependency of 8.3% (p = 0.024) in tPA-treated patients.

ECASS III: European Cooperative Acute Stroke Study III (N Engl J Med 2008;359:1318–1329)

821 patients with acute ischemic stroke 3–4.5 hr from onset, randomized to tPA 0.9 mg/kg or placebo. Exclusions: Age ≥80, severe stroke (NIHSS >25), the combination of prior stroke and diabetes, oral anticoagulant (whether INR elevated or not), platelet count <100,000.

tPA-treated patients had a 7% absolute increase (15% relative) in the odds of minimal or no disability (p = 0.04). Symptomatic ICH greater in treated group (2.4% vs. 0.2%; p = 0.008).

Table 15.4. Randomized Thrombolysis Trials (cont'd)




EMS: Emergency Management of Stroke Bridging Trial (Stroke 1999;30:2598–2605)

35 patients with acute ischemic stroke <3 hr were randomized to IV plus local IA tPA vs. intraarterial tPA alone.

IV/IA treatment resulted in higher recanalization rates but no difference in outcome at 7 days or 3 months. The rate of symptomatic ICH was similar between groups.

IMS: Interventional Management of Stroke Trial (Stroke 2004;35:904–912)

80 patients with an NIHSS ≥10 at baseline received reduced dose IV rt-PA (0.6 mg/kg, 60 mg maximum over 30 min) within 3 hr of symptom onset. All patients then underwent an angiogram. Additional tPA was administered at the site of the thrombus (maximum dose, 22 mg) over 2 hr of infusion or until thrombolysis.

3-month mortality in IMS patients (16%) was numerically lower but not statistically different than the mortality of placebo- or tPA-treated patients in the NINDS rt-PA stroke trial. The rate of symptomatic ICH (6.3%) in IMS subjects was similar to that of rt-PA–treated subjects but higher than the rate in placebo-treated subjects in the NINDS rt-PA stroke trial.IMS subjects had a signifi cantly better outcome at 3 months than did NINDS placebo-treated subjects for all outcome measures (OR, ≥2).

IMS II: Interventional Management of Stroke Trial (Stroke 2007;38:2127–2135; AJNR 2008;29:582–587)

81 patients with a baseline NIHSS ≥10 received reduced dose IV tPA (0.6 mg/kg) within 3 hr of symptom onset, followed by angiography. For subjects with an arterial occlusion at angiography, additional rt-PA was administeredvia an EKOS micro-infusion catheter (with ultrasound) or a standard microcatheter at the site of the thrombus, up to a total dose of 22 mg over 2 hr of infusion or until thrombolysis.

The rate of symptomatic ICH in IMS II subjects was 9.9%. Recanalization was achieved in 41% of patients within 1 hr, and 68% within 2 hr. Recanalization was strongly correlated with a good clinical outcome. Compared to patients in the placebo arm of the NINDS trial, IMS II subjects had signifi cantly better outcomes at 3 months (OR, 2.7) and better outcomes than did NINDS rt-PA–treated subjects. A randomized trial of standard IV rt-PA as compared with a combined IV and IA approach is now underway (IMS III).





MAST-E: Multicentre Acute Stroke Trial-Europe (N Engl J Med 1996;335:145)

310 patients with MCA-territory stroke <6 hr were randomized to SK (1.5 million units) IV or placebo.

No difference in mortality or disability at 6 months. However, there was higher mortality in SK-treated patients at 10 days (34% vs. 18%), mainly due to hemorrhagic transformation of ischemic infarcts.

MAST-I: Multicentre Acute Stroke Trial-Italy (Lancet 1995;346:1509)

622 patients with acute ischemic stroke <6 hr were randomized to SK (1.5 million units), aspirin (300 mg/d), both, or neither.

SK with or without aspirin was associated with high mortality rates at 10 days. Nonsignifi cant trend toward less disability in SK- and aspirin-treated patients at 6 months.

NINDS tPA trial: National Institute of Neurological Disorders and Stroke tPA trial (N Engl J Med 1995;333:1581; Stroke 1998;29:288)

291 patients with acute ischemic stroke <3 hr were randomized to tPA (0.9 mg/kg IV over 1 hr; 10% of total dose given as a bolus; maximum dose, 90 mg) or placebo and assessed for 4-point improvement in NIHSS score or the resolution of neurologic defi cit within 24 hr. 333 patients received IV tPA within 3 hr of symptom onset and were assessed for functional and clinical outcome at 3 months. Almost 50% of patients were treated within 90 min of stroke onset.

No difference in neurologic improvement at 24 hr, but patients given tPA were 30% more likely than controls to have minimal or no disability at 3 months, despite more symptomatic ICH at 36 hr (6.4% vs. 0.6%). Overall, there was no difference in mortality at 3 months (tPA 17% vs. placebo 21%). No vascular imaging was reported.

PROACT II: Prolyse in Acute Cerebral Thrombo- embolism II (JAMA 1999;282:2003)

180 patients with acute ischemic stroke <6 hr and MCA occlusion on angiography were randomized to r-proUK (9 mg IA) plus heparin vs. heparin alone.

At 90 days, 40% of patients given pro-urokinase had no or slight disability compared to 25% given heparin only (p = 0.04). Recanalization rates (66% vs. 18%) and symptomatic ICH (10.9% vs. 3.1%) were higher in the proUK group. Median time from onset of symptoms to IA therapy was >5 hr.





ACAS: Asymptomatic Carotid Atherosclerosis Study (JAMA 1995;273:1421)

1662 patients with asymptomatic carotid artery stenosis ≥60% were randomized to CEA or aspirin 325 mg/d.

5-year risk of stroke was 11% with medical treatment and 5.1% with surgery (53% risk reduction). Perioperative morbidity/mortality was low (2.3%). Nonsignifi cant (17%) risk reduction in women.

ACST: MRC Asymptomatic Carotid Surgery Trial (Lancet 2004;363:1491–1502)

3120 patients randomized to immediate CEA or indefi nite deferral, followed for an average of 3.4 years.

Risk of stroke or death within 30 days of CEA was 3.1%; 5-year stroke risk (excluding perioperative events) was 3.8% in surgical group vs. 11% in medically treated group. Event rate in medically treated women was lower (7.48% at 5 years) but still statistically signifi cant (p = 0.02).

ECST: European Carotid Surgery Trial (Lancet 1991;337:1235; Lancet 1998;351:1379; Stroke 2003;34:514)

2518 patients with mild (0–29%), moderate (30–69%), or severe (70–99%) carotid stenosis and carotid-territory TIA or mild stroke within 6 months were randomized to carotid surgery vs. best medical treatment.

For those with severe stenosis (n = 778), the risk of disability or fatal stroke at 3 years was 11% in the medical group vs. 6% in the surgical group. The risk of major stroke or death at 3 years for stenosis >80% was 26.5% for the medical group vs. 14.5% for the surgical group. Endarterectomy for mild stenosis was associated with an unfavorable outcome.

NASCET I: North American Symptomatic Carotid Endarterectomy Trial (N Engl J Med 1991;325:445)

695 patients with 70–99% carotid stenosis and TIA or minor stroke within 120 days were randomized to carotid surgery plus postoperative antiplatelet therapy vs. medical therapy.

Surgery resulted in a marked reduction in ipsilateral stroke at 2 years (9% vs. 26%, p <0.001).

NASCET II: North American Symptomatic Carotid Endarterectomy Trial (N Engl J Med 1998;339:1415)

2226 patients with moderate stenosis (30–49% or 50–69%)and TIA or nondisabling ipsilateral stroke were randomized to surgery or medical therapy.

For patients with 50–69% stenosis, surgery resulted in a modest reduction in ipsilateral stroke at 5 years (15.7% vs. 22.2%; p = 0.045). Benefi t was greater in men than in women. For patients with 30–49% stenosis, there was no signifi cant benefi t to surgery.

Table 15.5. Carotid Endarterectomy Trials




VA Asymptomatic Carotid Artery Stenosis Trial (N Engl J Med 1993;328:221)

444 men with asymptomatic carotid stenosis >50% were randomized to CEA plus antiplatelet therapy vs. medical therapy alone.

Average follow-up, 48 months. Rate of ipsilateral stroke: 4.7% in the surgical group vs. 9.4% in the medical group. Rate of ipsilateral stroke or TIA: 8% in surgical group vs. 20.6% in the medical group. No difference in combined endpoint of stroke and death in fi rst 30 postoperative days.

VA Study (JAMA 1991;266:3289)

189 patients with TIAs or minor stroke were randomized to CEA vs. medical treatment.

Trial stopped prematurely because of NASCET and ECST results. Benefi t in surgical group for endpoints of stroke and crescendo TIAs.


Angioplasty of Intracranial Occlusion Resistant to Thrombolysis in Acute Ischemic Stroke (Neurosurgery 2001;48:1282–1288)

49 patients underwent IA therapy for acute stroke, 9 of whom were treated with balloon angioplasty after inadequate recanalization with thrombolytic infusion.

Angioplasty was successful in 55%.

ARCHER: Acculink for Revascularization of Carotids in High-Risk Patients (J Vasc Surg 2006;44(2):258–268)

581 patients at high surgical risk for CEA were treated by carotid stenting with distal embolic protection (added for the last 422 patients).

Procedural success: 93%. 30-day results: stroke or death—6.6%; stroke, death, MI—8.3%. Results well below historical similar cohort undergoing CEA.

CAVATAS: Carotid and Vertebral Artery Transluminal Angioplasty Study (Lancet 2001;357:1729–1737)

504 patients with carotid stenosis were randomized to endovascular treatment (stent, 26%; balloon angioplasty, 74%) or CEA.

There was no difference between stent/balloon group and CEA group with respect to disabling stroke or death at 30 days (6.4% vs. 5.9%) or ipsilateral stroke at 3 years. Severe (70–99%) ipsilateral stenosis at 1 year was more common after endovascular treatment (14% vs. 4%, p <0.001).

Table 15.5. Carotid Endarterectomy Trials (cont'd)

Table 15.6. Cerebral Angioplasty/Stent Trials



Table 15.6. Cerebral Angioplasty/Stent Trials (cont'd)


Endovascular Treat ment of Unresponsive Vasospasm in Subarachnoid Hemorrhage (Presented at 26th International Stroke Conference February, 2002)

45 patients with SAH and vasospasm unresponsive to hypervolemia and hypertensive therapy were treated with angioplasty ± IA papaverine.

Angiographic improvement occurred in all patients. Cerebral infarction developed in 64%, and 27% of patients had minimal or no disability.

MERCI: Mechanical Embolus Removal in Cerebral Ischemia (Stroke 2005;36:1432–1440)

151 patients with large-vessel occlusions (51% MCA, 31% ICA, 9% vertebrobasilar), who underwent embolectomy with the MERCI retrieval device within 8 hr of symptom onset. Patients were ineligible for IV tPA.

Recanalization achieved in 46% of patients (ITT) and in 48% of patients in whom the device was deployed. Good neurologic outcomes were much more likely in patients who recanalized than in patients who did not (46% vs. 10%, RR = 4.4; p <0.0001), with reduced mortality (32% vs. 54%; p = 0.01). Symptomatic ICH occurred in 7.8% of patients, and procedural complications occurred in 7.1%.

Multi MERCI: Mechanical Embolus Removal in Cerebral Ischemia (Stroke 2008;29:1205–1212)

Prospective single arm trial of thrombectomy in patients with large-vessel stroke treated within 8 hr of symptom onset. 164 patients treated. Pretreatment with IV tPA was permitted in the trial, and patients were enrolled if there was persistent large-vessel occlusion; this occurred in 29% of the cohort. IA tPA was permitted if the MERCI retriever did not result in recanalization.

32% of patients had ICA occlusion, 60% MCA, and 8% vertebral. Recanalization occurred in 57.3% of patients with the MERCI retriever and in 69.5% of patients after adjunctive therapy (IA tPA or mechanical). Favorable clinical outcomes occurred in 36% of patients. A favorable outcome strongly correlated with recanalization; 49% of patients who recanalized had a favorable outcome, but only 9.6% of those who did not recanalize (RR = 5; p <0.001). Symptomatic ICH occurred in 9.8%, and signifi cant procedural complications occurred in 5.5%.




SAPPHIRE: Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (N Engl J Med 2004;351:1493–1501)

344 patients with asymptomatic carotid stenosis ≥80% or symptomatic carotid stenosis ≥50% and at least 1 high-risk feature (age >80 years, heart failure, severe COPD, previous CEA with restenosis, previous radiation or radical neck surgery, or lesions distal or proximal to usual cervical locations) were randomized to carotid stenting with distal embolic protection vs. CEA.

The primary endpoint (the cumulative incidence of a major cardiovascular event at 1 year—a composite of death, stroke, or MI within 30 days after the intervention, or death or ipsilateral stroke between 31 days and 1 year) occurred in 12.2% of patients who received stenting vs. 20.1% of patients who underwent endarterectomy (p = 0.004 for noninferiority, and p = 0.053 for superiority).

Table 15.7. Miscellaneous Stroke Trials


COOL-AID: Induced Hypothermia in Acute Ischemic Stroke (Stroke 2001;32:1847–1854)

10 patients with major (NIHSS score >15) ischemic stroke <6 hr undergoing thrombolysis were treated with hypothermia (32°C) for 12–72 hr.

Death occurred in 3 patients. At 90 days, the MRS score was 3.1 ± 2.3.

ISAT: International Subarachnoid Aneurysm Trial (Lancet 2002;360:1267–1274)

2143 patients with ruptured intracranial aneurysms were randomized to neurosurgical clipping or endovascular treatment with platinum coils.

Improved outcome with endovascular coiling: 23.7% of patients randomized to coiling were dead or dependent at 1 year vs. 30.6% in the neurosurgical clipping group (RRR, 22.6%; p = 0.0019).

Table 15.6. Cerebral Angioplasty/Stent Trials (cont'd)



Table 15.8. Hypertension Trials


ACCESS: Acute Candesartan Cilexetil Therapy in Stroke Survivors (Stroke 2003;34:1699–1703).

342 patients with acute stroke randomized to moderate BP reduction with candesartan vs. placebo.

12-month mortality and vascular events were signifi cantly lower in candesartan group (OR = 0.475; 95% CI = 0.252–0.895).

ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (JAMA 2002;288:2981 and 2000;283:1967)

33,357 patients ≥55 years with BP 140–170/90–109 mmHg and 1 other cardiovascular risk factor were randomized to chlorthalidone, lisinopril, amlodipine or doxazosin, with or without pravastatin. Primary endpoint: fatal CHD or nonfatal MI. Mean follow-up: 4.9 years.

No difference in primary outcome between chlorthalidone, lisinopril, and amlodipine. Compared to doxazosin, chlorthalidone resulted in less combined cardiovascular disease (21.8% vs. 25.5%; p <0.001) due to less heart failure (4.45% vs. 8.13%; p <0.001).

ANBP2: Second Australian National Blood Pressure Study (N Engl J Med 2003;348:583–592)

6083 hypertensives aged 65–84 years were treated with an ACE inhibitor or diuretic (specifi c agent chosen by treating physician). Follow-up: 4.1 years.

ACE inhibitor reduced the risk of major cardiovascular events by 11% (p = 0.05) compared to diuretics despite similar reductions in BP.

ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (Lancet 2005;366:895–906)

19,257 hypertensive men and women aged 40–79 years with ≥3 factors were randomized to amlodipine (5–10 mg/d)± perindopril (4–8 mg/d) or to atenolol (50–100 mg/d) ± bendrofl umethiazide-K (1.25–2.5 mg/d).

The study was stopped prematurely after 5.5 years of median follow-up. Fewer individuals on the amlodipine-based regimen had a primary endpoint (429 vs. 474; p = 0.1052), stroke (327 vs. 422; p = 0.0003), total cardiovascular events and procedures (1362 vs. 1602; p <0.0001), and all-cause mortality (738 vs. 820; p = 0.025). The incidence of developing diabetes was also lower on the amlodipine-based regimen (567 vs. 799; p <0.0001).




CAPPP: Captopril Prevention Project Study (Lancet 1999;353:611–616)

10,985 patients aged 25–66 years with DBP ≥100 mmHg were randomized to captopril or conventional therapy (diuretics, beta blockers).

No difference in primary composite endpoint (MI, stroke, cardiovascular death) between groups. In the ACE inhibitor-based group, there were fewer cases of new-onset diabetes; among diabetics, MI was reduced by 66%.

HOT: Hypertension Optimum Treatment Study (Lancet 1998;351:1755–1762)

18,790 patients aged 50–89 years with DBP 100–115 mmHg were randomized to three target DBP levels (≤80, ≤85, ≤90 mmHg) ± aspirin 75 mg/d. Felodipine was given as fi rst-line therapy with addition of an ACE inhibitor or beta blocker as needed. Patients were also randomized to low-dose aspirin (75 mg/d) or placebo.

No differences in major cardiovascular events among target groups, although differences in achieved DBP were small (85, 83, 81 mmHg). Lowest incidence of cardiovascular events occurred at a DBP of 82.6 mmHg. Among 1501 diabetics, cardiovascular mortality was reduced by 67% in those assigned to the ≤80 mmHg target group compared to the ≤90 mmHg group. Aspirin reduced the rate of major cardiovascular events (MI, stroke, or cardiovascular death) by 15% (p = 0.03).

LIFE: Losartan Intervention for Endpoint Reduction (Lancet 2002;359:995–1003)

9193 patients with BP 160–200/95–115 mmHg and LVH were randomized to losartan or atenolol. Endpoint: death, MI, or stroke. Followup: 4.8 years.

Losartan reduced the primary endpoint by 16% (11% vs. 13%; p = 0.021), driven by a reduction in stroke (5% vs. 7%; p = 0.001). Among 1326 patients with isolated systolic hypertension, losartan reduced the risk of cardiovascular mortality, stroke, and total mortality by 46%, 41%, and 28%, respectively. Losartan was also associated with less new-onset diabetes and was better tolerated.

NORDIL: Nordic Diltiazem Study (Lancet 2000;356:359)

10,881 patients with DBP ≥100 mmHg were randomized to diltiazem vs. diuretics, beta blockers, or both. Endpoint: stroke, MI, or cardiac death.

No differences between groups at 4.5 years.

Table 15.8. Hypertension Trials (cont'd)




PRoFESS trial See p. 147. See p. 147.

PROGRESS: Perindopril Protection Against Recurrent Stroke Study (Lancet 2001;358:1033–1041)

6105 patients with stroke or TIA within 5 years were randomized to perindopril ± indapamide or placebo. Follow-up: 4 years.

Active treatment reduced recurrent stroke by 28% (10% vs. 14%; p <0.0001) and total major vascular events by 26% in patients with and without hypertension. Combination therapy with perindopril plus indapamide reduced recurrent stroke by 43%; perindopril alone had no signifi cant impact.

SHEP: Systolic Hypertension in the Elderly Program (JAMA 1991;265:3255)

4736 patients with pure systolic hypertension (avg. BP = 170/77 mmHg) were randomized to chlorthalidone 15 mg or placebo.

At 5 years, active drug therapy reduced the incidence of fatal and nonfatal stroke by 36% and mortality from coronary disease by 27%. Absolute risk reduction over 4.5 years was 1.4%. All-cause mortality was unaffected.

STOP-2: Swedish Trial in Old Patients with Hypertension-2 (Lancet 1999;354:1751–1756)

6614 patients (age 70–84) with SBP ≥180 mmHg and/or DBP ≥105 mmHg were randomized to conventional antihypertensive drugs (atenolol, metoprolol, HCTZ) or newer drugs (enalapril, lisinopril, felodipine, isradipine). Endpoint: fatal stroke, fatal MI, other fatal cardiovascular disease at 5 years.

No difference in primary endpoint between groups.

Syst-Eur: Isolated Systolic Hypertension in Other Patients (Lancet 1997;350:757–764;Lancet 1998;352:1347; N Engl J Med 1999;340:677)

4695 patients ≥60 years with SBP 160–219 and DBP <95 mmHg randomized to active treatment (nitrendipine 10–40 mg/d ± enalapril 5–20 mg/d) or placebo. 2-year followup.

Active treatment reduced mean SBP by 10.1 mmHg and DBP by 4.5 mmHg. Drug therapy reduced total stroke by 42%, nonfatal stroke by 44%, and cardiac events by 26%. Elderly diabetics derived greatest benefi t with 55–76% reductions in mortality, stroke, and cardiac events.






UKPDS: United Kingdom Prospective Diabetes Study (BMJ 1998;317:703; BMJ 1998;317:713)

1148 type 2 diabetics were randomized to tight vs. less-tight BP control using either an atenolol-based program (usually with a diuretic added) or a captopril-based program (with a diuretic added if needed to control BP). Median followup: 8.4 years.

Tight control group (mean BP, 144/82 mmHg) with 24–47% reductions in retinopathy, proteinuria, MI, heart failure, and stroke compared to less-tight control group (BP, 154/87 mmHg). No difference in outcomes between atenolol-based and captopril-based groups.

Table 15.9. Dyslipidemia and Other Risk Reduction Trials


4S: Scandinavian Simvastatin Survival Study (Lancet 1994;344:1383)

4444 male and female CHD patients with elevated total cholesterol (mean, 261 mg/dL) were randomized to simvastatin (mean dosage, 27.4 mg/d) or placebo. Mean baseline LDL, 188 mg/dL. Mean followup: 5 years.

All-cause mortality was reduced by 30%, CHD mortality was reduced by 42% in the simvastatin group. Angioplasty, bypass surgery, and major coronary event rates were all decreased by 30–40% on active therapy.

AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study (JAMA 1998;279:1615)

6605 men and women with no history of coronary disease, total cholesterol 180–264 mg/dL, and HDL <45 mg/dL for men or <47 mg/dL for women were randomized to lovastatin (20–40 mg/dL) or placebo. Many had average lipid levels, and only 17% of trial participants would have qualifi ed for drug therapy according to ATP II guidelines. Mean cholesterol, 221 mg/dL, mean LDL, 150 mg/dL, mean HDL, 36 mg/dL. Followup: 5.2 years.

Incidence of primary endpoint—fi rst acute major coronary event (fatal and nonfatal Ml, unstable angina, sudden cardiac death)—was reduced by 37% with lovastatin. Revascularization procedures (CABG, PTCA) were reduced by 33%.



Table 15.9. Dyslipidemia and Other Risk Reduction Trials (cont'd)


ASCOT-LLA: Anglo- Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (Lancet 2003;361:1149–1158)

19,342 men and women aged 40–79 years with hypertension and ≥ 3 other risk factors were randomized to amlodipine (5–10 mg/d) ± perindopril (4–8 mg/d) or to atenolol (50–100 mg/d) ± bendrofl umethiazide-K (1.25–2.5 mg/d). 10,305 of these patients with normal orslightly elevated total cholesterol (≤250 mg/dL) were randomized to atorvastatin 10 mg/d or placebo. Primary endpoint: CHD death or nonfatal MI.

Atorvastatin arm of trial was prematurely stopped at 3.3 years due to a signifi cant 36% reduction in the primary endpoint (p = 0.0005). Benefi ts were apparent within the fi rst year. Fatal/nonfatal stroke and total cardiovascular/coronary events were also signifi cantly reduced by 21–27% with atorvastatin. At 1 year, atorvastatin reduced total cholesterol and LDL cholesterol by 24% and 35%, respectively.

CAPRIE: Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (Lancet 1996;348:1329)

19,185 patients with atherosclerotic vascular disease (MI within 35 days or ischemic stroke within 6 months before randomization, or established peripheral arterial disease) were randomized to clopidogrel (75 mg/d) or aspirin (325 mg/d).

At 1.6 years, clopidogrel reduced the combined endpoint of new ischemic stroke, new MI, or other vascular death by 8.7% relative to aspirin (p = 0.043). Benefi t was greatest in patients with peripheral artery disease (especially if prior MI).

CARDS: Collaborative Atorvastatin Diabetes Study (Lancet 2004;364:685–696)

2388 type 2 diabetics aged 40–75 without overt heart disease and LDL cholesterol <160 mg/dL were randomized to atorvastatin (10 mg/d) or placebo.

Trial halted 2 years early due to a signifi cantly lower risk of fatal and nonfatal coronary events, stroke, and revascularization procedures in patients receiving atorvastatin. Subjects receiving atorvastatin had 37% lower cardiovascular events (p = 0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 patients treated for 4 years. In atorvastatin-treated patients, acute coronary events were reduced by 36%, coronary revascularizations by 31%, and strokes by 48%.




CARE: Cholesterol and Recurrent Events (N Engl J Med 1996;335:1001)

4159 MI survivors with total cholesterol <240 mg/dL (mean, 209 mg/dL) and LDL 115–174 mg/dL (mean, 139 mg/dL) were randomized to pravastatin 40 mg/d or placebo.

At 5 years, pravastatin reduced coronary death and recurrent MI (primary endpoint) by 24%, coronary bypass surgery by 26%, coronary angioplasty by 23%, and stroke by 31%.

GISSI: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (Lancet 1999;354:447)

11,324 men and women with prior MI were randomized to fi sh oil (1 gm/d), vitamin E (300 mg/d), both, or placebo for 3.5 years. Baseline LDL was 138 mg/dL.

Fish oil alone or in combination reduced all-cause mortality by 20%, sudden death by 45%, and cardiovascular death by 30%. Vitamin E produced no benefi t on these endpoints.

HATS: HDL Atherosclerosis Treatment Study (N Engl J Med 2001;345:1583)

160 men under age 65 and women under age 70 with CHD and isolated low HDL (<35 mg/dLin men, <40 mg/dL in women) were randomized to simvastatin plus niacin, antioxidants, both, or placebo. Followup: 3 years.

First cardiovascular event (death, MI, stroke, revascularization) was reduced by simvastatin plus niacin (3% vs. 21% for antioxidants, 14% for simvastatin plus niacin combined with antioxidants, and 24% for placebo).

HOPE: Heart Outcomes Prevention Evaluation (N Engl J Med 2000;342:145 [ramipril]; N Engl J Med 2000;342:154 [vitamin E]; Circulation 2001;103:919 [SECURE study])

9297 men and women aged ≥55 years with either vascular disease or diabetes plus 1 other cardiovascular risk factor but without LV dysfunction or heart failure were randomized to ramipril (10 mg/d) vitamin E (400 IU) both, or placebo and followed for a mean of 5 years.

Composite of MI, stroke, or death from cardiovascular causes was reduced by 22% with ramipril (14.0% vs. 17.8%; p <0.001). Ramipril also reduced death from cardiovascular causes by 26% and all-cause mortality by 16% and slowed progression of atherosclerosis (carotid ultrasound). No benefi t for vitamin E.





HPS: Heart Protection Study (Lancet 2002;360:7 [simvastatin]; Lancet 2002;360:23 [antioxidant vitamins]; Lancet 2003;361:2005 [diabetics])

20,536 men and women with coronary disease, peripheral arterial disease, cerebrovascular disease, or diabetes and with total cholesterol >135 mg/dL were randomized to simvastatin (40 mg/d) or placebo, and to antioxidant vitamins (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene) or placebo. Mean total cholesterol, 228 mg/dL; mean LDL, 131 mg/dL; mean HDL, 41 mg/dL. Included 3424 patients with baseline LDL <100 mg/dL. Followup: 5 years.

Simvastatin resulted in a signifi cant 12% reduction in all-cause mortality due largely to an 18% reduction in coronary death. Simvastatin also reduced MI by 38%, stroke by 25%, and revascularization procedures by 22%. Benefi ts were apparent in all subgroups, including those with baseline LDL <100 mg/dL. Simvastatin reduced the risk of a fi rst major vascular event by 33% among 2912 diabetics without arterial occlusive disease and by 27% among 2426 diabetics with LDL <116 mg/dL. Simvastatin was extremely safe and well tolerated. No benefi ts were observed with antioxidant vitamins.

LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease (N Engl J Med 1998;339:1349; N Engl J Med 2000;343:317; Lancet 2002;359:1379)

9014 men and women with cholesterol ranging from 155 to 271 mg/dL and a history of MI or unstable angina prior to study enrollment were randomized to pravastatin (40 mg/d) or placebo. Median LDL was 150 mg/dL. Mean followup: 6 years.

CHD death (primary endpoint) was reduced by 24%, CHD death or nonfatal MI by 24%, all-cause mortality by 22%, need for coronary revascularization by 20%, and stroke by 19% in the pravastatin group. Benefi t was sustained at 8 years.

LRC-CPPT: Lipid Research Clinics Coronary Primary Prevention Trial (JAMA 1984;251:351; JAMA 1984;251:365)

3806 men aged 35–59 years without CHD with total cholesterol ≥265 mg/dL (mean, 292 mg/dL) and LDL ≥190 mg/dL (mean, 216 mg/dL) were treated with diet and randomized to cholestyramine 24 gm/d or placebo. Followup: 7.4 years.

The primary endpoint of CHD death or nonfatal MI was reduced by 19%, and LDL was reduced by 12% with cholestyramine compared with placebo. Separate analysis of cholestyramine patients indicated that each 11% decrement in LDL was associated with a 19% decrement in CHD risk.





Lyon Diet Heart Study (Lancet 1994;343:1454; Circulation 1999;99:779)

605 men and women with prior MI were randomized to a Mediterranean-style diet (including high monounsaturated fat) or no dietary advice and followed up for 1–4 years (mean 27 months).

The primary endpoint of cardiovascular death or nonfatal MI was signifi cantly reduced by 73% in patients in the diet group; all-cause mortality was signifi cantly reduced by 70% in this group. Protective effect was maintained at 4 years.

PROSPER: Prospective Study of Pravastatin in the Elderly at Risk (Lancet 2002;360:1623)

5804 men and women aged 70–82 years with vascular disease or cardiovascular risk factors were randomized to pravastatin (40 mg/d) or placebo. Baseline total cholesterol criterion was 155–348 mg/dL. Mean followup: 3.2 years.

Composite primary endpoint of coronary death, nonfatal MI, or fatal or nonfatal stroke was reduced by 15% with pravastatin (14.1% vs. 16.2%; p = 0.014). Stroke incidence was similar between treatment groups, but TIAs were reduced by 25% with pravastatin (2.7% vs. 3.5%; p = 0.051).

SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels (N Engl J Med 2006;355:549–559)

4731 patients who had had a stroke or TIA within 1–6 months before study entry, but no known CHD, and with LDL cholesterol levels of 100–190 mg/dL randomized to 80 mg of atorvastatin per day or placebo. Median follow-up was 4.9 years.

The mean LDL level during the trial was 73 mg/dL among patients receiving atorvastatin and 129 mg/dL among patients receiving placebo. There was an absolute difference of 2.2% (RRR,16.8%; p = 0.03) at 5 years in fatal or nonfatal stroke among patients randomized to atorvastatin. There were 22 more hemorrhagic strokes in the atorvastatin group.





VA-HIT: Veterans Affairs HDL Intervention Trial (N Engl J Med 1999;341:410; JAMA 2001;285:1585)

2531 men with CHD (prior MI, angina with ischemia, coronary revascularization, or angiographic evidence), HDL ≤40 mg/dL (mean, 32 mg/dL), LDL ≤140 mg/dL (mean, 111 mg/dL), and triglycerides ≤300 mg/dL (mean, 160 mg/dL) were randomized to slow-release gemfi brozil (1200 mg/d) or placebo and followed for a median of 5.1 years.

MI or cardiac death (primary endpoint) was 22% lower in patients receiving gemfi brozil. The combined endpoint of CHD death, nonfatal MI, and stroke was reduced by 24%. The benefi t of gemfi brozil was only partly explained by the change in HDL.

WOSCOPS: West of Scotland Coronary Prevention Study (N Engl J Med 1995;331:1301; Circulation 2001;103:357)

6595 men without prior MI aged 45–64 years with total cholesterol ≥252 mg/dL (mean, 272 mg/dL) were randomized to pravastatin (40 mg/d) or placebo. Mean LDL was 192 mg/dL. Mean followup: 5 years.

31% reduction in CHD death and/or nonfatal MI (primary endpoint). Pravastatin reduced all-cause mortality 22% (p = 0.051) and reduced the risk of developing diabetes by 30% (p = 0.042).

Table 15.10. Neuroprotection Trials


ALIAS (Stroke 2006;37:2107–2114)

82 patients with acute ischemic stroke (NIHSS score of ≥6) received 25% albumin beginning within 16 hr of stroke onset. Six successive ALB dose tiers were assessed (range, 0.34–2.05 gm/kg). In 42 of these patients, standard-of-care IV tPA was also given. Effi cacy outcomes were determined at 3 months. These results have led to a multicenter, randomized, placebo-controlled effi cacy trial of ALB in acute ischemic stroke—the ALIAS Phase III Trial.

The highest three dose titers of albumin were compared with the lowest three and with historic controls from the NINDS rt-PA trial. The probability of good outcome (defi ned as MRS score 0–1 or NIHSS score 0–1 at 3 months) at the highest three albumin doses was 81% greater than in the lower-dose tiers and was 95% greater than in the comparable NINDS rt-PA trial cohort. The tPA-treated patients who received higher-dose albumin were three times more likely to achieve a good outcome than were the patients who received lower-dose albumin.





Citicoline: A Phase III randomized effi cacy trial of 2000 mg citicoline in acute ischemic stroke patients. (Neurology 2001;57:1595–1602)

899 patients with presumed MCA strokes and NIHSS score ≥8 randomized to receive citicoline 1000 mg bid for 6 weeks or placebo, within 24 hr of symptom onset. Citicoline is an intermediary in the biosynthesis of the membrane phospholipid phosphatidylcholine and enhances the synthesis of this lipid in the brain.

There were no between-group differences on the planned primary analysis; the percent of patients with a ≥7-point NIHSS score change at 90 days (placebo 51%, citicoline 52%). There were no between-group differences on the other planned secondary analyses at 90 days, including mortality. However, post hoc analyses showed more patients made an “excellent recovery” measured by an MRS score of 0 or 1 (placebo, 20%; citicoline, 26%; p = 0.025).

SAINT I: Stroke Acute Ischemic NXY-059 Treatment (N Engl J Med 2006;354:588–600)

1722 patients with acute ischemic stroke were randomly assigned to receive a 72-hr infusion of placebo or IV NXY-059, a free radical scavenging agent, within 6 hr after the onset of stroke. Patients could receive IV tPA as part of standard-of-care treatment.

NXY-059 signifi cantly improved by 20% (p = 0.038) the overall distribution of scores on the MRS. Mortality and rates of adverse events were each similar in the two groups. NXY-059 did not improve neurologic functioning as measured by the NIHSS, nor functional outcome as measured by the Barthel Index.There were fewer ICHs among patients receiving NXY-059 in addition to tPA, compared with patients receiving tPA without NXY-059.

SAINT II: Stroke Acute Ischemic NXY-059 Treatment (N Engl J Med 2007;357:562–571)

3306 patients with acute ischemic stroke were randomized to a 72-hr infusion of IV NXY-059 or placebo within 6 hr after the onset of stroke symptoms. IV tPA was permissible per standard of care.

The distribution of scores on the MRS did not differ between the group treated with NXY-059 and the placebo group (p = 0.33). There was no evidence of effi cacy for any of the secondary endpoints. Among patients treated with IV tPA, there was no difference between the NXY-059 group and the placebo group in the frequency of symptomatic or asymptomatic hemorrhage.

Table 15.10. Neuroprotection Trials (cont'd)



Table 15.11. Intracerebral Hemorrhage Trials


Factor VII: Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage (N Engl J Med 2005;352:777–785)

399 patients with ICH diagnosed by CT randomized to receive placebo (96 patients) or 40 mcg of rFVIIa per kg of body weight (108 patients), 80 mcg/kg (92 patients), or 160 mcg/kg (103 patients) within 1 hr after the baseline scan. Patients randomized within 3 hr of symptom onset. The primary outcome measure was the percent change in the volume of the ICH at 24 hr. Clinical outcomes were assessed at 90 days.

Hematoma volume increased more in the placebo group than in the rFVIIa groups (29% vs. 11–16% for the treatment groups; p = 0.01). 69% of placebo-treated patients died or were severely disabled, as compared with 49–55% of rFVIIa patients (p = 0.004).Mortality at 90 days was 29% for patients who received placebo, compared with 18% in the three rFVIIa groups combined (p = 0.02). 7% of patients had serious thromboembolic adverse events (including MI or stroke).

Factor VII: Effi cacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage (N Engl J Med 2008;358:2127–2137)

841 patients with ICH randomized to placebo (268 patients), 20 mcg of rFVIIa per kg (276 patients), or 80 mcg of rFVIIa per kg (297 patients) within 4 hr after the onset of stroke. The primary endpoint was poor outcome, defi ned as severe disability or death according to the MRS 90 days after stroke.

Treatment with 80 mcg of rFVIIa per kg resulted in a signifi cant reduction in growth in volume of the hemorrhage. Despite this reduction in bleeding, there was no signifi cant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 mcg of rFVIIa per kg, and 29% in the group receiving 80 mcg/kg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 mcg/kg of rFVIIa than in the placebo group.




STICH: Surgical Trial in Intracerebral Haemorrhage (Lancet 2005;365:387–397)

1033 patients with ICH randomized to early evacuation (within 24 hr of randomization) or conservative treatment. Exclusions: Patients with cerebellar hemorrhage, bleeding due to probable aneurysm or AVM, or bleeding that extended from a supratentorial source into the brainstem.

At 6 months, 26% of patients randomized to surgery had a favorable outcome vs. 24% treated conservatively.

Table 15.11. Intracerebral Hemorrhage Trials (cont'd)



SECTION 4

FILM LIBRARY

Chapter 16. Film Library . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .175


Figure 1.

Bilateral venous infarctions (arrows) on diffusion imaging, in a 29-year-old patient who developed severe headache 3 days post partum.

Chapter 16

Film Library


Figure 2.

Abrupt cutoff of fl ow (arrow) is visible in the superior sagittal sinus in the same patient as in Figure 1.



Figure 3.

Initial CT scan in a 82-year-old woman who presented to the hospital within 1 hour of onset of left hemiparesis, left fi eld cut, and left neglect. NIHSS score was 11. This CT scan is entirely normal. Within 6 hours of treatment, NIHSS score diminished to 4, with resolution of the neglect and fi eld cut, and improvement in the hemiparesis. By 3 months, the patient had mild left facial droop and left arm drift but no other fi ndings.

Chapter 16. Film Library 177


Figure 4.

Follow-up CT scan in the same patient 24 hours after the initial scan. There is interval development of hypodensity (arrow) in the right basal ganglia and internal capsule, consistent with acute stroke.



Figure 5.

Diffusion MRI (same patient as in Figures 3 and 4) performed 72 hours after the onset of symptoms. In addition to the large lesion in the basal ganglia—comparable to the lesion seen on the CT scan (Figure 4)—there are two small cortically based infarcts not viable on the CT. These are strongly indicative of proximal MCA embolism that dissolved and moved distally.



Figure 6.

Apparent diffusion coeffi cient map (same patient as in Figures 3–5). The bright signal on diffusion (Figure 5) and dark signal here on ADC are diagnostic of an acute ischemic infarct.



Figure 7.

A left MCA/ACA watershed infarct (arrow) seen on diffusion imaging in an 80-year-old patient who presented with proximal right arm and leg weakness.



Figure 8.

Severe left carotid stenosis (arrow); same patient as in Figure 7.



Figure 9.

Left carotid artery status stent (arrow), with improvement of stenosis (same patient as in Figures 7 and 8).



Figure 10.

CT angiogram of left carotid artery showing extracranial dissection (arrow) with a tapered cutoff of the vessel. This is a 45-year-old man who developed a headache and left-side ptosis with meiosis (Horner syndrome) after rough play with his son.



Figure 11.

Angiogram showing nearly absent proximal left MCA fl ow in a 75-year-old man with atrial fi brillation, not on anticoagulation, who presented to the emergency room within 3 hours of development of global aphasia.



Figure 12.

Post IA tPA angiogram, same patient as in Figure 11, showing recanalization of the left MCA. The patient was discharged home on warfarin, without any neurologic defi cits.



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TEXTBOOKS AND MONOGRAPHS Batjer HH, Caplan LR, Friberg L, Greenlee RG, Kopitnik

TA, Young WL (eds). Cerebrovascular Disease. Phila-delphia: Lippencott-Raven, 1997.

Bogousslavsky J, Caplan LR (eds). Stroke Syndromes, 2 nd edition. Cambridge: Cambridge University Press, 2001.

Bogousslavsky J, Caplan LR (eds). Uncommon Causes of Stroke. Cambridge: Cambridge University Press, 2001.

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Caplan LR, Dyken ML, Easton JD (eds). The American Heart Association Family Guide to Stroke: Treat-ment, Recovery, and Prevention. New York: Times Books, Random House, 1993.

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Datjer JJ, Caplan LR, Friberg L (eds). Cerebrovascular Dis-ease. Philadelphia: Lippencott–Raven, 1997.

Kase C, Caplan LR (eds). Intracerebral Hemorrhage. Boston: Butterworth–Heinemann, 1994.

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Welch M, Weir B, Caplan LR, Reis D, Siesjo B (eds). Primer on Cerebrovascular Diseases. San Diego: Academic Press, Inc., 1997.



A CE inhibitors . . . . . . . 134 Acute coronary syndromes

(ACS), treatment of . . . . . . . . . . . . 106–107

Acute ischemic stroke, thrombolytic therapy for . . . . . . . . . . . . . . . . . 31

Acute mild stroke . . . 71–72 Acute subdural

hematomas . . . . . . . . . 42 AF, see Atrial fi brillation Angioplasty . . . . . . 135–136 Anticoagulation with

warfarin . . . . . . . . . 64–65 Antiobesity drugs . . . 93–94 Antioxidants . . . . . . . . . 136 Antiplatelet agents with

warfarin . . . . . . . . . 64–65 Antiplatelet therapy . . . . 60

for acute stroke . . . . . . 149–152

combination . . . . 105–108 for ischemic stroke

. . . . . . . . 18, 102–109 mechanism of . . . . . . . 104 for TIA . . . . . . . . 145–149

Antithrombotic therapy for ischemic stroke . . . . . . . . . 109–111

Arterial revascularization . . . . . . . . . . . . . . 135–136

Aspirin . . . . . . . . . 102–104 plus clopidogrel . . . 60, 106 plus dipyridamole

. . . . . . . . . 69–70, 106 Asymptomatic carotid artery

stenosis (ACAS) trial . . . . . . . . . . . . 52, 135

Asymptomatic carotid surgery trial (ACST) . . . 135

Atherothrombosis . . . . . 102 Atherothrombotic vascular

disease . . . . . . . . . . . . . 76 Atrial fi brillation (AF) . . . . 22

nonrheumatic, stratifi cation of . . . . . . . . . . . . . 110

stroke prophylaxis in . . . . . . . . . . 142–144

Atrial myxoma . . . . . . . . . 23

B ile acid sequestrants . . . . . . . . 131

Blood pressure (BP) . . . . 115 factors affecting . . . . . 117 goals to control . . . . . . 119 JNCVII classifi cation in

adults . . . . . . . . . . 115 management of . . . 32, 61 measurement

technique . . . . 116–117 Body mass index

(BMI) . . . . . . . . . . . 90, 91 BP, see Blood pressure Brain imaging, treatment of

stroke on . . . . . . . . . . . 57

C ardiac evaluation . . . . . 59 Cardiomyopathy . . . . . . . 23 Cardiovascular disease

(CVD), 114, see also Cerebrovascular disease risk reduction in . . . 76–77

Carotid endarterectomy (CEA) . . . . . 52–53, 135 156–157 overuse in asymptomatic

patients . . . . . . . . . . 58 Carotid stenosis . . . . . . . . 59

Carotid stenting . . . . 53, 135–136

Carotid surgery . . . . . . . . 70 CEA, see Carotid

endarterectomy Cerebellar hemorrhage . . 42 Cerebral angiography . . . . 9 Cerebral angioplasty/stent

trials . . . . . . . . . . 157–159 Cerebrovascular disease

risk of stroke for individuals with . . . . . . . . . . . . . 76

risk reduction in . . . 76–77 Cholesterol absorption

inhibitor . . . . . . . . . . . 132 Chronic hypertension . . . 61 Chronic subdural hematomas

. . . . . . . . . . . . . . . . . . . 43 Citicoline, clinical

trials of . . . . . . . . . . . . . 137 Clopidogrel

. . . . . . . 69–70, 104–105 aspirin plus . . . . . . . . . . 60

Computed tomography angiography (CTA) . . . . . 8

Computerized tomography (CT) . . . . . . . . . . . . . . . . 8

Craniotomy for supratentorial ICH . . . . . . . . . . . . . 68–69

CVD, see Cardiovascular disease

D iabetes mellitus, control of . . . . . . . . . . 134

Dietary options for cardiovascular risk

reduction . . . . . . 83–84 for LDL-lowering . . . 83–84

Diets . . . . . . . . . . . . . . . . 80

INDEX

193 I n d e x

77890_IDXx_Print.indd 19377890_IDXx_Print.indd 193 10/12/09 11:32:49 AM10/12/09 11:32:49 AM

mediterranean . . . . 84–85 components

of . . . . . . . . . 86–87 incorporating into daily

living . . . . . . . 87–88 therapeutic lifestyle

changes . . . . . . . 80–81 components

of . . . . . . . . . 81–82 Dipyridamole, extended-

release . . . . . . . . . . . . . 69 Dissolution of clot . . . . . . 29 Drug therapy

for dyslipidemia . . . . . . . . . . . 128–132

for treatment of hypertension combination therapy. .121 initial therapy

. . . . . . . . . 119–120 intensifi cation of

. . . . . . . . . 120–121 stepdown

therapy . . . . . . . 121 Dyslipidemia . . . . . 163–168

diagnosis, evaluation, and treatment of . . . . . 124

drug therapy for . . . . . . . . . . . 128–132

genetic . . . . . . . . . . . . 125

E chocardiography . . . . . . 9 Electrocardiography . . . . . . 9 Electroencephalography . . 9 Elevated

triglyceride . . . . . 126–128 causes of . . . . . . . . . . 126 treatment of . . . . . . . . 129

Extended-release dipyridamole . . . . . . . . . 69

Extracranial circulation . . . 58 Extracranial-intracranial

(EC-IC) bypass . . . . . . . . 53

Extradural hematomas . . 43 Extradural hemorrhage . . 36

F ibric acid derivatives . . 131 Fish oil, low-dose . . . . . . 135 Folic acid . . . . . . . . . . . . 136

G enetic dyslipidemia . . 125

H emicraniectomy for malignant MCA stroke . . .67

Hemorrhage cerebellar . . . . . . . . . . . 42 extradural . . . . . . . . . . . 36 intracerebral . . . . . . . . . 36

causes of . . . . . . . . . 42 by hypertension . . .41–42

subarachnoid . . . . . . . . 36 complications

cardiac . . . . . . . . . 40 hydrocephalus . . . . 40 hyponatremia . . . . 41 increased intracranial pressure . . . . . . . . 40 intracerebral hematoma . . . . . . 40 rebleeding . . . . . . . 40 vasospasm . . . . . . 40

subdural . . . . . . . . . . . . 36 Hemorrhagic stroke,

. . . . . . . . . . . . . . . . 36–38 Heparin therapy . . . . . . . 19 HMG-CoA reductase

inhibitors . . . . . . . 61,130 Holter monitoring . . . . . . . 9 Homocysteine . . . . . . . . 136 Hormone replacement

therapy . . . . . . . . . . . . 137 Hydrocephalus . . . . . . . . 40 Hypertension . . . . . . . . . 114

chronic . . . . . . . . . . . . . 61 diagnosis and evaluation

of . . . . . . . . . 114–119

intracerebral hemorrhage by . . . . . . . . . . . 41–42

overtreatment in acute stroke . . . . . . . . . . . 58

pseudohypertension . . 118 secondary . . . . . . 118–119

causes of . . . . 118–119 detection . . . . . . . . 118

treatment by drug therapy . . . . . . . 115, 119–121

trials . . . . . . . . . . 160–163 white-coat . . . . . . 117–118

Hyponatremia . . . . . . . . . 40

I ntra-arterial thrombolysis . . . . . . . . . . 6

Intra-arterial tissue plasminogen activator (IA tPA) . . . . . . . . . . 65–66

Intracerebral hemorrhage . . . . . . . . . 36 causes of . . . . . . . . . . . 42 by hypertension . . . 41–42 trials . . . . . . . . . . 170–171

Intracranial circulation . . . 58 Intravenous tissue

plasminogen activator (IV tPA) . . . . . . . . . . 65–66

Ischemic attack, transient, see Transient ischemic attack (TIA)

Ischemic stroke . . . . . . . . 60 acute

heparin therapy of . . 19 pathophysiology

of . . . . . . . . . . . 103 thrombolytic therapy for

. . . . . . . . . . . . . . 31 antiplatelet therapy for, 18

. . . . . . . . . . . 102–109 antithrombotic therapy

for . . . . . . . . . 109–111 clinical features of . . 13–15



common sites and mechanisms of . . . . . 12

hemorrhagic stroke vs. . . 5 risk factors for . . . . . . . . 77 role of platelet in . . . . 102 therapeutic measures

to prevent recurring of . . . . . . . . . . . 20–24

treatment of . . . . . . 15–18 vs. hemorrhagic stroke . . 5

L acunar stroke . . . . . . . . 24–25, 61

LDL cholesterol . . . . 125 treatment . . . . . . 126–128

Lipoprotein analysis . . . . 124 Lumbar puncture (LP) . . . . 9 Lytic complications,

management of . . . . . . 32

M agnetic resonance angiography (MRA) . . . . . 8

Magnetic resonance imaging (MRI) . . . . . . . . . . . . . . . 8

Malignant MCA stroke, hemicraniectomy for . . . 67

Mediterranean diets . . . . . . . . . . . . 84–85 components of . . . . 86–87 incorporating into daily

living . . . . . . . . . 87–88 MERCI retriever . . . 7, 28, 66 Metabolic syndrome . . . 125 Mild stroke, acute . . . 71–72

N ational Institutes of Health (NIH), stroke scale of . . . . . . . . . . . . . 33

Neuroprotection trials . . . . . . . . . . . . . . 168–169

Nicotinic acid (Niacin) . . .130 Non-HDL cholesterol,

. . . . . . . . . . . . . . 125, 126

Nonrheumatic atrial fi brillation, stratifi cation of . . . . . . . . . . . . . . . . 110

O besity classifi cation of . . . . 90, 91 drug therapy for . . . 93–94 evaluation of . . . . . . . . . 91 treatment of . . . . . . 91–92

Overweight, see Obesity

P aradoxical embolism . . . 23 Patent foramen ovale (PFO)

closure . . . . . . . . . . . . . 65 Physical activity, benefi ts of

. . . . . . . . . . . . . . . . 89–90 Prophylactic measures . . . 60 Pseudohypertension . . . 118

R andomized thrombolysis trials . . . . . . . . . . 152–155

Risk reduction trials 163–168 Ruptured berry aneurysms

. . . . . . . . . . . . . . . . 38–39 embolization/coiling

of . . . . . . . . . . . . . . 39

S econdary hypertension causes of . . . . . . 118–119 detection . . . . . . . . . . 118

Selective estrogen receptor modulator (SERM) . . . . 137

Smoking cessation . . . 94–95 drug therapy for . . . 98–99 strategies for assisting

patients in . . . . . 96–97 Stroke

classifi cation of . . . . . . . . 4 clinical evaluation of . . . 7–8 clinical presentation of . . .16 initial evaluation of . . . . . 6 management of . . . . . . . 6

Stroke mimics . . . . . . . . . 57

Stroke prophylaxis in atrial fi brillation . . . . . . 142–144

Stroke scale of NIH . . . . . 33 Subacute subdural

hematomas . . . . . . . . . . 42 Subarachnoid

hemorrhage . . . . . . . . . . 36 complications

cardiac . . . . . . . . . . . 40 hydrocephalus . . . . . 40 hyponatremia . . . . . . 41 increased intracranial

pressure . . . . . . . 40 intracerebral hematoma

. . . . . . . . . . . . . . 40 rebleeding . . . . . . . . 40 vasospasm . . . . . . . . 40

ruptured AV malformation . . . . . . . . . . . . . 39–40

ruptured berry aneurysms . . . . . . . . . . . . . 38–39

treatment of . . . . . . 39–40 Subdural hematomas,

chronic . . . . . . . . . . . . . 43 Subdural hemorrhage . . . 36 Surgical evacuation for

supratentorial ICH . . . . . . . . . . . . . 68–69

Symptom onset, time of . . 58

T arget organ damage . . .118 Temporal course of

stroke, work-up and treatment of . . . . . . . . . 57

Therapeutic lifestyle changes (TLC) diet . . . . . . . . 80–81 components of . . . . 81–82

Thrombolysis, intra-arterial . . .6 Thrombolysis trials,

randomized . . . . 152–155 Thrombolytic therapy . . . 57

for acute ischemic stroke . . . . . . . . . . . . 31

I n d e x 195


dosing and administration of . . . . . . . . . . . . . . 30

TIA, see Transient ischemic attack

Ticlopidine . . . . . . . . . . 105 Tissue plasminogen activator

(tPA) intra-arterial . . . . . . 65–66 intravenous . . . . . . . 65–66 risk of . . . . . . . . . . . . . . 72

Transcranial Doppler (TCD) . . . . . . . . . . . . . . . 8

Transient ischemic attack (TIA) . . . . . . . . . . . . . . . 25 antiplatelet therapy

for . . . . . . . . . 145–149 Transient neurologic

defi cits . . . . . . . . . . . . . 57 Trials

AAASPS . . . . . . . . . . . 145 AAT . . . . . . . . . . . . . . 145 AbESST . . . . . . . . . . . . 149 AbESST II . . . . . . . . . . 150 ACAS . . . . . . . . . . . . . 156 ACCESS . . . . . . . . . . . 160 ACST . . . . . . . . . . . . . 156 ACTIVE A . . . . . . . . . . 142 ACTIVE W . . . . . . . . . . 142 AFASAK . . . . . . . . . . . 142 AFCAPS/TexCAPS . . . . 163 AICLA . . . . . . . . . . . . . 145 ALIAS . . . . . . . . . . . . . 168 ALLHAT . . . . . . . . . . . 160 ANBP2 . . . . . . . . . . . . 160 ARCHER . . . . . . . . . . . 157 ASCOT . . . . . . . . . . . . 160 ASCOT-LLA . . . . . . . . . 164 ASK . . . . . . . . . . . . . . 152 ATLANTIS . . . . . . . . . . 153 BAATAF . . . . . . . . . . . 142 CAPPP . . . . . . . . . . . . 161 CAPRIE . . . . . . . . 145, 164

CARDS . . . . . . . . . . . . 164 CARE . . . . . . . . . . . . . 165 CAST . . . . . . . . . . . . . 150 CATS . . . . . . . . . . . . . 145 CAVATAS . . . . . . . . . . 157 COOL-AID . . . . . . . . . . 159 DIAS-2 . . . . . . . . . . . . 153 Dutch TIA . . . . . . . . . . 146 EAFT . . . . . . . . . . . . . . 143 ECASS . . . . . . . . . . . . 153 ECASS II . . . . . . . . . . . 153 ECASS III . . . . . . . . 28, 153 ECST . . . . . . . . . . . . . . 156 EMS . . . . . . . . . . . . . . 154 ESPS . . . . . . . . . . . . . . 146 ESPS-2 . . . . . . . . . . . . 146 Factor VII . . . . . . . . . . 170 GISSI . . . . . . . . . . . . . 165 HAEST . . . . . . . . . . . . 150 HATS . . . . . . . . . . . . . 165 HOPE . . . . . . . . . . . . . 165 HOT . . . . . . . . . . . . . . 161 HPS . . . . . . . . . . . . . . 166 IMS . . . . . . . . . . . . . . 154 IMS II . . . . . . . . . . . . . 154 ISAT . . . . . . . . . . . . . . 159 IST . . . . . . . . . . . . . . . 151 LIFE . . . . . . . . . . . . . . 161 LIPID . . . . . . . . . . . . . . 166 LRC-CPPT . . . . . . . . . . 166 MAST-E . . . . . . . . . . . . 155 MAST-I . . . . . . . . . . . . 155 MATCH . . . . . . . . . . . . 146 MERCI . . . . . . . . . . . . 158 NASCET I . . . . . . . . . . 156 NASCET II . . . . . . . . . . 156 NINDS tPA . . . . . . . . . 155 NORDIL . . . . . . . . . . . . 161 PICSS . . . . . . . . . . . . . 146 PROACT II . . . . . . . . . . 155 PRoFESS . . . . . . . . . . . 147 PROGRESS . . . . . . . . . 162

PROSPER . . . . . . . . . . . 167 SAINT I . . . . . . . . . . . . 169 SAINT II . . . . . . . . . . . 169 SALT . . . . . . . . . . . . . . 147 SAPPHIRE . . . . . . . . . . 159 SHEP . . . . . . . . . . . . . . 162 SPAF . . . . . . . . . . . . . . 143 SPAF II . . . . . . . . . . . . 143 SPAF III . . . . . . . . . . . . 144 SPARCL . . . . . . . . . . . . 167 SPORTIF-III . . . . . . . . . 144 SPORTIF-V . . . . . . . . . . 144 STAT . . . . . . . . . . . . . . 151 STICH . . . . . . . . . . 68, 171 STOP-2 . . . . . . . . . . . . 162 TASS . . . . . . . . . . . . . . 148 TOAST . . . . . . . . . . . . 152 UKPDS . . . . . . . . . . . . 163 UK-TIA . . . . . . . . . . . . 148 VA-HIT . . . . . . . . . . . . 168 WARSS . . . . . . . . . . . . 148 WASID . . . . . . . . . . . . 149 WASID-R . . . . . . . . . . . 148 WOSCOPS . . . . . . . . . 168

U nruptured aneurysm . . .52

V alvular heart disease . . . . . . . . . . . . . 22

Vasospasm . . . . . . . . . . . 40 Vertebral artery

stenting . . . . . . . . . . . . 53

W arfarin . . . . . . 109–111 antiplatelet agents/

anticoagulation with . . . . . . . . . . 64–65

stroke/death rate in . . . 64 Weight control, 90, see also

Obesity White-coat hypertension

. . . . . . . . . . . . . . 117–118



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