Prevention of Stroke or Recurrent Stroke, Including Management of Risk Factors

1
Prevention of Stroke or Recurrent Stroke,
Including Management of Risk Factors
2
Evaluation for Cause and Prevention of Stroke
Recurrence
3
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)

4
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.

5
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 gt60 yrs, diabetes mellitus,
  focal symptoms of weakness or speech impairment,
  TIA lasting gt/ 10 minutes
• Importance of rapid diagnosis and treatment of
  TIA
• Source Johnston SC, Gress D, Browner WS, et al.
  JAMA 2000 284 2901-2906

6
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

7
Early Stroke Worsening Recurrence or Evolving
Stroke?

• US NINDS National Stroke Data Bank
• Approximately 75 of cases with early worsening
  of stroke deficit have deterioration due to the
  incident stroke
• Common within the first 3-4 days after stroke
  onset and with larger artery atherosclerotic
  disease
• 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• Source Unpublished (cited in Sacco RL et al.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

8
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

9
Putative Predictors of Late Stroke Recurrence

• Age
• Hypertension
• Heart Disease
• Atrial Fibrillation
• Heavy Alcohol Use

• CHF
• Diabetes Mellitus
• Hyperglycemia
• Prior stroke/TIA

10
Stroke Recurrence and Mortality After Ischemic
Stroke

• At 30 days 8
• At 1 year 22
• At 5 years 45
• Immediate cause of death is vascular disease in
  about 60
• For hemorrhagic stroke at 30 days lt/ 50
• Source Sacco RL et al. Neurology 1994 44
  626-634

11
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 31 123-127

12
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)?

13
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 patients overall
  clinical condition and severity of illness, and
  patient/family input is it appropriate to obtain
  additional diagnostic studies?

14
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

15
Diagnostic Evaluation for Cause of Recurrent
Stroke-2

• Follow principles in other sections of this
  course
• Section 1 Clinical Diagnosis of Stroke
• Section 2 Neuroimaging Evaluation

16
Pharmacologic Therapy for Recurrent Stroke
Prevention Antithrombotic Agents
17
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

18
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)

19
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

20
Aspirin As Acute Stroke Therapy IST and CAST

• Aspirin dose 300 mg or 160 mg/day
• Results Modest Benefits
• Reduction of recurrent ischemic stroke 7/1000
• Reduction of death w/o further stroke 4/1000
• Reduction of stroke/death in hospital 9/1000
• Hemorrhagic stroke or hemorrhagic stroke
  transformation 2/1000
• IST International Stroke Trial
• CAST Chinese Acute Stroke Trial

21
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

22
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

23
Risk of Hemorrhagic Stroke in Persons Taking
Aspirin Collaborative Trials

• Hemorrhagic stroke risk appears to be low
• Increase in hemorrhagic stroke 12/10,000
• Reduction in myocardial infarction 137/10,000
• Reduction in ischemic stroke 39/10,000
• Source He J, Whelton PK, Vu B, Klag MJ. JAMA
  1998 280 1930-1935

24
Aspirin, ACE-I and NSAIDs Antagonistic
Interactions?

• At aspirin doses of gt/ 300mg, aspirins 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

25
Efficacy of Ticlopidine, Clopidogrel, and Aspirin
plus Extended-Release Dipyridamole vs. Aspirin
Alone Indirect Comparisons
26
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 NNTnumber needed
  to treat Source Albers G et al. Chest 2001
  119300S-320S

27
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

28
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

29
American College of Chest PhysiciansRecommendatio
n 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

30
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)

31
Oral Anticoagulation for Recurrent Stroke
Prevention
32
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
  fractionundergoing further testing in Warfarin
  vs. Aspirin in Reduced Cardiac Ejection Fraction
  study)

33
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 gt 1
• systolic function
  factor warfarin
• Low lt65yrs, no other factors Aspirin
• Aspirin dose is 325 mg/day

34
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

35
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
• 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 al. N
  Engl J Med 2001 345 1444-51

36
Recently Completed or Ongoing Recurrent Stroke
Prevention Studies in Adults

• Womens 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 J
  Med 2001 345 1243-1249

37
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

38
Stroke Risk Factor Reduction Recommendations

• Risk Factor Goal Recommendation
• Hypertension lt140/90 JNC VI guidelines
• Smoking Cessation Counseling,
• 
  nicotine, bupropion
• Diabetes HbA1c ADA guidelines
• lt7
• Alcohol lt/ 2 drinks Counseling
• lt130/80-85 if diabetic

39
Stroke Risk Factor Reduction Recommendations
(cont.)

• Risk Factor Goal Recommendation
• Physical 30-60 min. Moderate exercise
• Inactivity most days
• Weight lt/ 120 of Diet, exercise
• ideal body wght
• Lipids LDL lt100mg/dl NCEP III
• 
  guidelines
• if symptomatic atherosclerotic carotid artery
  disease

40
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?

41
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. Lancet
  2001 358 1033-41

42
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

43
Carotid Endarterectomy (CEA)
44
Indications for CEA

• Condition Stenosis Indicated? NNT
• Symptomatic 70-99 yes 8
• Symptomatic 50-69 yes 20
• Symptomatic lt50 no 67
• Asymptomatic 60-99 yes 83
• indicated in high risk patients
• indication subject to controversy
• Source Gorelick PB. Stroke 1999 30 1745-1750

45
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)

46
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

47
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

48
Angioplasty vs. Carotid Endarterectomy (CEA) in
CAVATAS
Outcome Angioplasty CEA RRR (95 CI)
1. Nondisabling Stroke at 30d 3.6 4.0 9 (-114,62)
2. Death or Disabling Stroke at 30d 6.4 5.9 8 (-45,110)
3. Death or Disabling Stroke at 3y 14.3 14.2 0.8 (-34,54)
(source ACP Journal Club Nov/Dec 2001, pg 91)
49
Management Controversies

• PFO
• Antiphospholipid Antibodies

50
Atrial Septal Abnormalities and 4-Year
Recurrence Risk on Aspirin
Patients ages 18-55 years with cryptogenic stroke

• No PFO or atrial septal aneurysm
• Patent foramen ovale (PFO) alone
• PFO and atrial septal aneurysm

• 4.2
• 2.3
• 15.2

Source Mas et al. N Engl J Med 2001,
3451740-6.
51
PICSS Substudy Warfarin vs. Aspirin
WARFARIN ASPIRIN RR (95 CI) P value
ENTIRE PICSS COHORT
With PFO (N203) 16.5 (N97) 13.2 (N106) 1.29 (0.63-2.64) 0.5
No PFO (N398) 13.4 (N195) 17.4 (N203) 0.80 (0.49-1.33) 0.4
CRYPTOGENIC COHORT
With PFO (N98) 9.5 (N42) 17.9 (N56) 0.52 (0.16-1.67) 0.3
No PFO (N152) 8.3 (N72) 16.3 (N80) 0.50 (0.19-1.31) 0.2
Preliminary data courtesy of Shunichi Homma, NY,
NY
52
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 in
  favor of aspirin

Source Levine et al. N Engl J Med
2002346752-63.
53
RR 0.99 RR
0.95 p 0.94
p 0.71
Interaction (TreatmentaPL) p0.91
Relative risk, p-values reflect analyses
adjusted for History of Cardiac Disease, History
of Stroke, Exercise Status and Age