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Evaluation for Cause and Prevention of Stroke Recurrence

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Evaluation for Cause and Prevention of Stroke Recurrence Powered By Docstoc
					  Prevention of Stroke or
Recurrent Stroke, Including
Management of Risk Factors
Evaluation for Cause and
  Prevention of Stroke
      Recurrence
Recurrent Stroke

• An important outcome for diagnosis and
  prevention
• Approximately 25% of the estimated 750,000
  strokes each year in the US are recurrences
• Must be distinguished from worsening or
  evolving stroke and medical complications of
  stroke (e.g., infection, electrolyte imbalance)
Risk of Stroke Recurrence
(percentage experiencing
stroke)
           After TIA    After Stroke
30 days       4-8%          3-10%

1 Year       12-13%        10-14%

5 Years      24-29%         25-40%
Source: Sacco RL, Wolf PA, Gorelick PB.
  Neurology 1999; 53 (supp 4): S15-S24.
High Risk of Early Stroke
Recurrence After TIA
  • Study of 1707 TIA patients who were
    evaluated in the ED of a large health care
    plan
  • 180 patients or 10.5% developed stroke
    within 90 days
  • 91 patients did so within 2 days
  • Predictors of stroke: >60 yrs, diabetes
    mellitus, focal symptoms of weakness or
    speech impairment, TIA lasting >/= 10
    minutes
  • Importance of rapid diagnosis and treatment
    of TIA
Recurrence Rate by Stroke
Subtype
      Athero Cardiac Emb      Lacune Etiol?
30 day 18.5%    5.3%           1.4%  3.3%

90 day 21.4%       8.6%        1.4%     4.8%

1 year   24.4%     13.7%       7.1%    13.2%

5 year   40.2%     31.7%       24.8% 33.2%

Source: Petty et al. Stroke 2000; 31: 1062-1068
Early Stroke Worsening:
Recurrence or Evolving
Stroke?
US NINDS National Stroke Data Bank
1. Approximately 75% of cases with early
   worsening of stroke deficit have
   deterioration due to the incident stroke
2. Common within the first 3-4 days after
   stroke onset and with larger artery
   atherosclerotic disease
3. Lacunes more likely to improve within the
   first 7-10 days after stroke onset
Source: Unpublished (cited in Sacco RL et al.
   Neurology 1999; 53 (Supp 4): S15-S24
Putative Predictors of Early
Stroke Recurrence
• Hypertension
• Elevated blood glucose


Source: Sacco RL, Shi T, Zamanillow MC,
 Kargman D. Neurology 1994; 25: 958-
 962 and Lai Min S, Alter S, Friday G,
 Sobel E. Stroke 1994; 25: 958-962
Putative Predictors of Late
Stroke Recurrence
•   Age                   •   CHF
•   Hypertension          •   Diabetes Mellitus
•   Heart Disease         •   Hyperglycemia
•   Atrial Fibrillation   •   Prior stroke/TIA
•   Heavy Alcohol Use
Stroke Recurrence and
Mortality After Ischemic Stroke
                        At 30 days: 8%
45%                     At 1 year: 22%
40%                     At 5 years: 45%
35%
                        Immediate cause of death
30%
25%
              30 days      is vascular disease in
20%
              1 year       about 60%
              5 years   For hemorrhagic stroke at
15%
10%                        30 days: </= 50%
 5%                     Source: Sacco RL et al.
 0%                        Neurology 1994; 44:
                           626-634
Stroke Recurrence and
Subsequent Stroke Subtype
 • May be difficult to determine stroke subtype
   as a comprehensive battery of diagnostic
   tests are not performed
 • Ischemic stroke begets ischemic stroke
   recurrence
 • Primary intracerebral hemorrhage (PICH)
   may give rise to recurrent hemorrhage in the
   same location or in the mirror image location,
   or an ischemic stroke
 • Annual recurrence rates after PICH: PICH
   (2.4%) vs. ischemia (3.0%)
 Source: Hill MD, Silver FL, Austin PC, Tu JV. Stroke 2000; 31: 123-
Diagnostic Evaluation for
Cause of Stroke Recurrence:
Pertinent Questions
• Early stroke recurrence?
• Worsening of incident stroke (e.g.,
  cerebral edema/mass effect,
  hemorrhagic infarction)?
• Medical complication of stroke (e.g.,
  infection, or electrolyte, fluid, glucose or
  other metabolic imbalance)?
Diagnostic Evaluation for
Cause of Stroke Recurrence:
Pertinent Questions
(continued)
• Was the prior stroke diagnostic work-up
  complete or were key diagnostic studies
  omitted?
• Am I providing the appropriate stroke
  treatment and preventatives based on the
  stroke mechanism?
• Based on the extent of the prior stroke
  diagnostic work-up, the patient’s overall
  clinical condition and severity of illness, and
Diagnostic Evaluation for
Cause of Recurrent Stroke-1
• CT or MRI to distinguish hemorrhagic stroke
  from ischemic stroke and extension of the
  incident stroke
• Diffusion-weighted MRI to diagnose new
  brain infarction
• Clues from general medical history and
  examination to establish possible medical
  complications and appropriate diagnostic
  studies
Diagnostic Evaluation for
Cause of Recurrent Stroke-2
•  Follow principles in other sections of
   this course:
1. Section 1: Clinical Diagnosis of Stroke
2. Section 2: Neuroimaging Evaluation
 Pharmacologic Therapy for
Recurrent Stroke Prevention:
   Antithrombotic Agents
Antiplatelet Therapy

• In the US, 4 approved antiplatelet
  agents for use in recurrent stroke
  prevention:
*Aspirin 50-325 mg/day
*Ticlopidine 250 mg twice daily
*Clopidogrel 75 mg/day
*Aspirin (25 mg) plus extended-release
  dipyridamole (200 mg) twice a day
Mechanism of Antiplatelet
Agents
Agent          Mechanism
Aspirin       Irreversible loss of cyclo-
                oxygenase activity
Ticlopidine/ Inhibition of ADP binding to
Clopidogrel   platelet glycoprotein IIb/IIIa
               receptor
Extended-      Inhibition of platelet phosphdiest.
Release         (increases c-AMP) potentiates
Dipyridamole prostacyclin, release of prostacyclin,
                and inhibits uptake and metabolism
                 of adenosine (platelet inhibitor and
                 vasodilating agent)
US FDA Ruling on Aspirin Dose
for Patients with Symptomatic
Cerebrovascular Disease
• Based on individual studies of efficacy of lower
  doses of aspirin for recurrent cerebral ischemia
  prevention and more favorable side effect
  profile with lower doses of aspirin
• Meta-analyses show no difference between
  high, medium and low doses of aspirin for
  prevention of major vascular events
• FDA recommendation: 50-325 mg/day
• Antiplatelet Trialists’ Collaboration: for
  stroke/TIA patients a 40/1000 reduction of
  major vascular events (stroke, MI, vascular
  death) over 3 years
Aspirin As Acute Stroke
Therapy: IST and CAST
• Aspirin dose: 300 mg or 160 mg/day
• Results: Modest Benefits
1. Reduction of recurrent ischemic stroke:
   7/1000
2. Reduction of death w/o further stroke:
   4/1000
3. Reduction of stroke/death in hospital:
   9/1000
4. Hemorrhagic stroke or hemorrhagic stroke
   transformation: 2/1000
IST= International Stroke Trial
Explanations for Aspirin
“Failure” in Clinical Practice
• Non-compliance
• Inadequate aspirin dose
• Resistance to aspirin (tachyphylaxis)
• Irrelevance of biological effect
• Other mechanisms
*Correlative studies of platelet function and
  clinical outcome are needed
Source: Helagason CM, Hoff JA, Kondos G,
  Brace LD. Stroke 1993; 24: 1458-1461
Aspirin vs. Placebo for
Prevention of Major Vascular
Events
• 15% relative risk reduction in favor of aspirin
  for stroke prevention
• 13% relative risk reduction in favor of aspirin
  for stroke, MI and vascular death prevention
Source: Johnston ES, et al. Arch Intern Med
  1999; 159: 1248-1253 and Algra A and Avan
  Gijn J. J Neurol Neurosurg Psychia 1996; 60:
  197-199
Risk of Hemorrhagic Stroke in
Persons Taking Aspirin:
Collaborative Trials
•  Hemorrhagic stroke risk appears to be
   low:
1. Increase in hemorrhagic stroke:
   12/10,000
2. Reduction in myocardial infarction:
   137/10,000
3. Reduction in ischemic stroke:
   39/10,000
Source: He J, Whelton PK, Vu B, Klag
   MJ. JAMA 1998; 280: 1930-1935
Aspirin, ACE-I and NSAIDs:
Antagonistic Interactions?
• At aspirin doses of >/= 300mg, aspirin’s
  effect of inhibiting prostaglandin
  synthesis may undo a beneficial effect
  of ACE-I (ACE-I increases bradykinin
  which promotes synthesis of
  vasodilating prostaglandins)
• Ibuprofen may competitively inhibit COX
  site and prevent aspirin effect
    Efficacy of Ticlopidine,
 Clopidogrel, and Aspirin plus
       Extended-Release
Dipyridamole vs. Aspirin Alone:
     Indirect Comparisons
Can We Achieve Better
Outcomes for Stroke with Non-
Aspirin Antiplatelet Agents?
• Agent ARR over Aspirin NNT p-value
Ticlopidine     2.5%          40     .02
Clopidogrel      0.8%         125     .28
Aspirin plus     3.0%          33     .006
Extended-release
Dipyridamole
ARR= absolute risk reduction NNT=number
  needed to treat Source: Albers G et al.
  Chest 2001; 119:300S-320S
Pitfalls of Indirect Antiplatelet
Comparisons
• Lack of head-to-head comparison of
  agents
• Different study epochs
• Different types of patients
• Different doses of aspirin

*A rigorous study with head-to-head direct
  comparisons is needed
Common and Key Side Effects
and Cost of Antiplatelet
Agents-1
• Aspirin: dyspepsia and GI bleeding,
  inexpensive
• Ticlopidine: diarrhea, GI symptoms, rash,
  neutropenia, TTP; cost-effective over aspirin
• Clopidogrel: more favorable side effect
  profile than ticlopidine and about as safe as
  aspirin; rash, diarrhea, GI symptoms, ?TTP;
  may be cost-effective over aspirin
• Aspirin plus Extended-Release
  Dipyridamole: headache, GI symptoms,
  dizziness; cost-effective over aspirin
American College of Chest
Physicians’Recommendation
for Initial Antiplatelet Therapy
• Any one of the following agents:
Aspirin
Aspirin plus extended-release
  dipyridamole
Clopidogrel

Source: Albers GW, Amarenco P, Easton
 JD, et al. Chest 2001; 119: 300S-320S
Combination Antiplatelet
Therapy for Recurrent Stroke
Prevention
• Aspirin plus extended-release
  dipyridamole is the only combination
  antiplatelet agent that is approved for
  prevention of stroke by the FDA
• Aspirin plus clopidogrel vs. clopidogrel
  is being tested in high risk stroke
  patients (MATCH study)
  Oral Anticoagulation for
Recurrent Stroke Prevention
Warfarin

• The primary indication is for stroke prevention
  in non-valvular atrial fibrillation (NVAF)
• Adjusted-dose warfarin reduces risk of stroke
  in AF by about 60% (vs. 20% for aspirin)
• Recommended INR range: 2.0-3.0, target=
  2.5
• Other indications: other cardiac sources of
  embolism (e.g., acute MI with thrombus,
  cardiomyopathy with low ejection
  fraction[undergoing further testing in Warfarin
  vs. Aspirin in Reduced Cardiac Ejection
  Fraction study])
Selection of Antithrombotic
Therapy in AF by Risk Strata
Risk    Risk Factors           Treatment
High     Prior stroke/TIA or   Warfarin
         systemic emb, HTN,
         poor LV function,
         +75yrs, rheumatic
          mitral valve disease
Medium 65-75yrs, DM and         1 factor:
 warfarin
          CAD w preserved LV or aspirin*; >
 1
          systolic function      factor:
 warfarin
Warfarin: A Double-Edged
Sword
• High risk reductions in NVAF
• Narrow therapeutic index drug
• Patient selection: compliant, reliable, and
  willing to undergo frequent INR monitoring
• Elderly stand to benefit most on warfarin but
  may have complicating conditions that make
  administration of warfarin problematic: prone
  to falls, cognitive impairment, visual
  difficulties, social isolation, etc
Warfarin Aspirin Recurrent
Stroke Study (WARSS)
•  Multicenter, double-blind, randomized trial of
   warfarin (INR 1.4-2.8) vs. aspirin 325
   mg/day in non-cardioembolic stroke patients
• Primary outcome: stroke or death within 2
   years
• Results:
1. No major difference in the 2 treatment
   groups for the primary outcome endpoint
   (17.8% warfarin vs. 16.0% aspirin) or major
   hemorrhage (2.22/100 pt-yrs warfarin vs.
   1.49/100 pt-yrs for aspirin
Source: Mohr JP, Thompson JLP, Lazar RM, et
Recently Completed or
Ongoing Recurrent Stroke
Prevention Studies in Adults
• Women’s Estrogen for Stroke Trial
  (WEST):Estradiol does not reduce mortality
  or stroke recurrence in postmenopausal
  women with cerebrovascular disease (higher
  risk of fatal stroke and worse neurologic and
  functional deficits)*
• African American Antiplatelet Stroke
  Prevention Study (AAASPS): Ticlopidine vs.
  aspirin
• Warfarin-Aspirin Symptomatic Intracranial
  Disease Study (WASID): Warfarin vs. aspirin
*Viscoli CM, Brass LM, Kernan W, et al. N Engl
Recurrent Stroke Prevention
Through Risk Factor Control
• Paucity of information regarding efficacy and
  safety of most risk factor therapies in
  recurrent stroke prevention
• Well-established methods to control risk
  factors for a first stroke are utilized to control
  risk factors to prevent a recurrent stroke
Source: Gorelick PB, Sacco RL, Smith DB, et
  al. JAMA 1999; 281: 1112-1120 and
  Goldstein LB, Adams R, Becker K, et al
  Stroke 2001; 32: 280-299
Stroke Risk Factor Reduction
Recommendations
Risk Factor Goal        Recommendation
Hypertension <140/90* JNC VI guidelines
Smoking        Cessation Counseling,
                            nicotine, bupropion
Diabetes        HbA1c      ADA guidelines
                 <7%
Alcohol         </= 2 drinks Counseling
*<130/80-85 if diabetic
Stroke Risk Factor Reduction
Recommendations (cont.)
Risk Factor       Goal       Recommendation
Physical                30-60 min. Moderate
   exercise
Inactivity                          most days
Weight      </= 120% of Diet, exercise
             ideal body wght
Lipids*     LDL <100mg/dl NCEP III
                                 guidelines
*if symptomatic atherosclerotic carotid artery
   disease
Effect of Blood Pressure
Reduction on Risk of Recurrent
Stroke
• Overview analysis shows a 19% recurrent
  stroke reduction; suggestive of benefit but
  inconclusive as small numbers of study
  subjects
• Perindopril Protection Against Recurrent
  Stroke Study (PROGRESS): Does perindopril
  (ACE-I) +/- indapamide (diuretic) reduce
  recurrent stroke risk among ischemic and
  hemorrhagic stroke patients who do or do not
  have hypertension and are treated for 4
  years?
PROGRESS Results

• Perindopril-based therapy was well tolerated
• Overall BP reduction in the active treatment
  group was about 9/4 mm Hg
• Stroke risk reduction was 28% (95% CI 17,
  38)
• Major vascular event risk reduction was 26%
  (95% CI 16, 34)
• Subgroups that benefited the most: dual
  therapy group, Asians, hypertensives,
  hemorrhagic stroke reduction
• Source: PROGRESS Collaborative Group.
Implications of PROGRESS

• Development of new guidelines for blood
  pressure control in recurrent stroke
  prevention (hypertensives and non-
  hypertensives benefited)
• Blood pressure and stroke: a continuum of
  risk
• Important implications for physicians who
  treat stroke patients
• Findings are complementary to HOPE study
  results
Carotid Endarterectomy (CEA)
Indications for CEA

Condition % Stenosis Indicated? NNT
Symptomatic 70-99%             yes     8
Symptomatic 50-69%             yes*    20
Symptomatic <50                no      67
Asymptomatic 60-99% yes**              83
*indicated in high risk patients
** indication subject to controversy
Source: Gorelick PB. Stroke 1999; 30: 1745-
   1750
Aspirin Dose After CEA

• Aspirin Carotid Endarterectomy (ACE) Trial
• Trend for reduction of stroke or death at 3
  months with lower dose aspirin (81 or 325
  mg) vs. higher dose aspirin (650 or 1300 mg)
  (p=.12)
• Statistically significant trend for reduction of
  stroke/MI/death at 3 months with lower dose
  aspirin vs. higher dose aspirin (p=.03)
• Source: Taylor and Thorpe. Lancet
  Conference 1998 (Montreal, Quebec,
  Canada)
Endovascular Interventions:
Angioplasty/Stenting and Coil
Embolism
• These procedures are considered
  experimental until more clinical
  evidence becomes available
• Randomized, controlled clinical trials will
  determine the efficacy and safety of
  these procedures vs. standard
  treatment
National Institute of Neurologic
Disorders and Stroke Ongoing
Clinical Trials
• Carotid Revascularization Endarterectomy vs. Stent
  Trial (CREST)
       A trial to compare carotid endarterectomy vs.
  carotid       stenting in symptomatic carotid occlusive
  disease
• Carotid Occlusion Surgery Study (COSS)
       A trial to compare STA-MCA anastomosis to best
       medical therapy in patients with symptomatic
  internal      carotid artery occlusion and hemodynamic
  failure       based on increased oxygen extraction
  fraction by PET study
Angioplasty vs. Carotid
Endarterectomy (CEA) in
CAVATAS
    Outcome        Angioplasty   CEA                RRR (95% CI)


1. Nondisabling       3.6%       4.0%                9% (-114,62)
Stroke at 30d

2. Death or           6.4%       5.9%                8% (-45,110)
Disabling Stroke
at 30d
3. Death or          14.3%       14.2%              0.8% (-34,54)
Disabling Stroke
at 3y


                                  (source: ACP Journal Club: Nov/Dec 2001, pg 91)
  Management
  Controversies
• PFO
• Antiphospholipid Antibodies
Atrial Septal Abnormalities and
4-Year Recurrence Risk on Aspirin
Patients ages 18-55 years with cryptogenic stroke

  • No PFO or atrial                 4.2%
    septal aneurysm
  • Patent foramen                   2.3%
    ovale (PFO)
    alone                            15.2%
  • PFO and atrial
    septal aneurysm
  Source: Mas et al. N Engl J Med 2001, 345:1740-6.
 PICSS Substudy: Warfarin vs. Aspirin
                  WARFARI        ASPIRIN RR (95% CI)      P value
                  N
ENTIRE
PICSS
COHORT
With PFO          16.5%          13.2%     1.29 (0.63-    0.5
(N=203)           (N=97)         (N=106)   2.64)
No PFO            13.4%          17.4%     0.80 (0.49-    0.4
(N=398)           (N=195)        (N=203)   1.33)
CRYPTOGENI
C COHORT
With PFO          9.5%           17.9%     0.52 (0.16-    0.3
(N=98)            (N=42)         (N=56)    1.67)
No PFO            8.3%            16.3%     0.50 (0.19-   0.2
  Preliminary data courtesy of   Shunichi Homma, NY, NY
                                  (N=80)    1.31)
Management of Stroke with
Antiphospholipid Antibodies
• Recent NEJM review article* suggests high
  dose warfarin is preferred treatment based
  on several small nonrandomized
  retrospective case series
• WARSS randomized substudy on
  antiphospholipid antibodies
  (720 patients with aPL)
  shows no significant difference and trend
   *Source: of aspirin
  in favorLevine et al. N Engl J Med 2002;346:752-63.
   WARSS/APASS: WARFARIN & ASPIRIN*
                                                  RR = 0.99                 RR = 0.95
                                                   p = 0.94                  p = 0.71
                                        40%
     Proportion with event at 2 Years




                                        35%
                                                                                                aPL+
                                        30%       26.2% 26.2%
                                        25%                                22.2% 21.8%          aPL-
                                        20%
                                        15%
                                        10%
                                        5%
                                        0%
                                                    Warfarin                  Aspirin
                                              (N=361 aPL+, 520 aPL-)   (N=359 aPL+, 530 aPL-)
                        Interaction (Treatment*aPL) p=0.91
*Relative risk, p-values reflect analyses adjusted for History of Cardiac Disease, History
of Stroke, Exercise Status and Age

				
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