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Now What???
The Secondary Prevention of
      Ischemic Stroke

     Jon Zlabek, MD, FACP
Learning Objectives
• Review the evidence-based management
  and guidelines for patients with transient
  ischemic attack ...
The Six “Big Boys”
•   Hypertension
•   Hypercholesterolemia
•   Smoking
•   Antiplatelet Therapy
•   Cardioembolic TIA/St...
The Scope of the Problem
• 795,000 people in the United States have a
  stroke each year
   – One every 40 seconds
• 150,0...
The Scope of the Problem
• Good News! From 1994-2004 the stroke
  rate FELL by 24.2% and the number of
  stroke deaths FEL...
Very High Risk Groups
                        Increase in Risk of Stroke
Site of Initial Event     vs. General Population
...
BIG BUCK$
        In 2010, for stroke-related
  expenses, Americans will pay an estimated


            73.7 BILLION
     ...
Transient Ischemic Attack
A brief episode of neurological dysfunction
caused by a focal disturbance of brain or
retinal is...
Stroke
An episode of neurological dysfunction
caused by a focal disturbance of brain
ischemia with clinical symptoms lasti...
TIA vs. Stroke
• The distinction is becoming less important
   – Share common pathological mechanisms
   – Preventative ap...
TIA vs. Stroke
• However, patients with TIA receive less
  aggressive diagnostic testing and treatment
  than stroke patie...
Transient Ischemic Attack
• About 15% of strokes are preceded by a
  TIA
• The risk of a stroke after a TIA is very
  high...
Transient Ischemic Attack
• Patients with TIA are very heterogenous in
  terms of symptoms, risk factors, and
  underlying...
Transient Ischemic Attack
• Isolated sensory or visual symptoms are
  associated with lower risk of subsequent
  stroke


...
“ABCD” Score
• “ABCD” Score                           • 7-day risk of CVA
   – Age > 60 (1 pt)                       – 6 =...
Express TIA Care Works!
• EXPRESS study
• Very thought-provoking study of patients with
  TIA or minor stroke

• Several t...
Express TIA Care Works!
• 91,000 patients in 9 primary care practices
  in Oxfordshire, UK

• Lifelong medical records are...
Phase 1 – Baseline Cohort
• Created an Express “TIA and Minor Stroke Clinic”
• Physicians were asked to refer all patients...
Phase 1 – Baseline Cohort
• Primary physician faxed an appointment
  request after they saw an appropriate patient

• The ...
Phase 1 – Baseline Cohort
• Performed usual studies:
   –   CT
   –   EKG
   –   Carotid Ultrasound
   –   Transthoracic E...
Phase 1 – Baseline Cohort
• Recommendations faxed to primary care
  physician within 24 hours:
   – Aspirin 75 mg/day or C...
Phase 1 – Baseline Cohort
• No treatment/prescriptions were given to the
  patient

• “Contact your primary care physician...
Phase 2 – Intervention Cohort
• No appointments necessary

• Physicians instructed to send all patients to
  the clinic th...
Phase 2 – Intervention Cohort
• All patients given 300 mg of aspirin in clinic
  or a 300 mg loading dose of clopidogrel
•...
Results of Express Care
• Phase 1 = 634 patients
• Phase 2 = 644 patients

• 95% of all referrals went to the Express
  Cl...
Results of Express Care
• Delay to assessment in Express Clinic:
   – Phase 1 = 3 days
   – Phase 2 = less than 1 day (p<0...
Results of Express Care
• Statin used:
   – Phase 1 = 65%
   – Phase 2 = 84% (p<0.0001)


• Aspirin + 30 days of clopidogr...
Results of Express Care
• On one or more blood pressure medications:
   – Phase 1 = 62%
   – Phase 2 = 83% (p<0.0001)


• ...
Results of Express Care
• 90-day risk of recurrent stroke
   – Phase 1 = 10.3%
   – Phase 2 = 2.1% (p=0.0001)
   – 80% red...
Stat TIA and Stroke Clinic
Now What???
• What can be done to combat this disease?
  –   Very common
  –   Deadly
  –   Extremely costly
  –   Devasta...
First Things First
Do the best you can to determine the
 mechanism of the ischemic event
Mechanisms of TIA/Stroke
•    Large artery atherosclerotic
•    Cardioembolic
•    Small-vessel disease
•    Hemorrhagic
•...
After you determine the mechanism,


          THEN . . .
Target the “Big Boys”
Hypertension


THE MOST IMPORTANT RISK
   FACTOR FOR STROKE




Stroke 2006;37:577-617
Hypertension
• Affects 31% of U.S. adults (~50 million)
• Control is poor:
   – 31% of patients with HTN are controlled
  ...
Hypertension
• Stroke risk rises linearly from 115/75 mmHg

• For every SBP elevation of 20 mmHg or
  DBP elevation of 10 ...
Hypertension
• About 60% of all strokes are attributable to
  hypertension
   – That’s 468,000 strokes per year in USA

• ...
We Missed the News Flash!

• Stroke & heart disease death rises linearly
  from 115/75 mmHg




JNC-7 NHLBI
We Missed the News Flash!
We Missed the News Flash!

• Stroke & heart disease death rises linearly
  from 115/75 mmHg

• 141/88 should take on a new...
Hypertension
• During and immediately after a
  stroke, blood pressure may transiently
  elevate in a compensatory fashion...
Hypertension
• Blood pressure can fall by as much as
  20/10 mmHg over the 10 days after stroke

• Antihypertensive therap...
Hypertension
• Recommended only to acutely lower blood
  pressure if:
   – SBP >220 mmHg, or
   – DBP >120-140 mmHg

• Use...
Hypertension
• After the acute event has passed, tight blood
  pressure control is essential
  – <130/80 mmHg if:
        ...
HTN Treatment after TIA/Stroke
• PROGRESS: Perindopril Protection
  against Recurrent Stroke Study

   – Currently is the ...
Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• 6105 patients with TIA or stroke within the
  past 5 ye...
Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• Primary outcome was fatal or non-fatal stroke
• Duratio...
Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• Baseline blood pressures:
   – Overall 147/86 mmHg
   –...
Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• Reduction in blood pressure vs. placebo
   – Active tre...
Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• Patients with primary endpoint of stroke:
   – Active t...
Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• In the active treatment group:
   –   Fewer major vascu...
Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• Combination therapy vs. perindopril only
   – Perindopr...
Perindopril Protection Against
Recurrent Stroke Study (PROGRESS)
• Hypertensive vs. Non-hypertensive groups
   – Reduction...
Hypertension Take Home Points
• Don’t acutely lower blood pressure after
  stroke

• Tight blood pressure control after th...
Hypertension Take Home Points
• Start thiazide plus ACE-I after stroke
  – Class I, LOE A

• Start blood pressure therapy ...
Hypercholesterolemia
• Cholesterol studies to date mainly looked at
  patients from a cardiac point of view

• Relative ri...
Hypercholesterolemia
• Statins were the most studied agents

• Niacin showed a reduction of
  cerebrovascular events in th...
Hypercholesterolemia
• SPARCL: Stroke Prevention by Aggressive
  Reduction in Cholesterol Levels
   –   4731 patients with...
SPARCL
• Followed for 4.9 years
• LDL levels at end of study
   – Atorvastatin group: 73 mg/dl
   – Placebo group: 129 mg/...
SPARCL
• Absolute risk reduction of major
  cardiovascular events: 3.5%
   – P = 0.002

• Small increase in hemorrhagic st...
Statins and Carotid Endarterectomy
• Retrospective study looking at the
  association of statin use before CEA and
  outco...
Statins and Carotid Endarterectomy
• Statin use was associated with:
   –   Perioperative stroke rate 1.2% vs. 4.5%
   –  ...
Statin Withdrawal After Stroke
• Eighty-nine patients taking a statin who
  suffered an ischemic stroke
• Randomized to at...
Statin Withdrawal After Stroke
• Measured:
   – Death/dependency
   – Early neurologic deterioration
   – Infarct volume

...
Statin Withdrawal After Stroke
• Statin withdrawal associated with:
   – 4.66-fold increased risk of death/dependency
   –...
Hypercholesterolemia Take
            Home Point
• Statin therapy should be started during
  hospitalization for patients ...
Smoking Is Bad
• Major independent risk factor for ischemic
  stroke
   – Doubling of risk compared with nonsmokers

• Ris...
Antiplatelet Therapy
Aspirin is Beneficial
• United Kingdom TIA Trial
   –   2435 patients with TIA or minor stroke
   –   Given 300 or 600 mg ...
Aspirin is Beneficial
• Swedish Aspirin Low-Dose Trial
   –   1360 patients with ischemic stroke
   –   Given 75 mg of asp...
What about Ticlopidine?
• Two major studies showed good results in
  TIA/stroke patients to prevent recurrence

• CATS (ti...
What about Ticlopidine?
• TASS (1300 mg aspirin vs. ticlopidine)
   – 2.3 years in duration
   – ARR = 2.6%; NNT = 39
   –...
Clopidogrel versus Aspirin in Patients at
 Risk of Ischemic Events (CAPRIE)

• 19,185 patients with recent myocardial
  in...
Lancet 1996;348:1329-39
Clopidogrel versus Aspirin in Patients at
 Risk of Ischemic Events (CAPRIE)

•    Endpoint reached with aspirin 5.83%
•   ...
Lancet 1996;348:1329-39
Clopidogrel versus Aspirin in Patients at
 Risk of Ischemic Events (CAPRIE)
• In the stroke subgroup (n=12,033 pt-yrs);
  ...
Clopidogrel + Aspirin?
• MATCH:
  Management of
  Athero-
  Thrombosis with
  Clopidogrel in
  High-Risk Patients with Tra...
Clopidogrel + Aspirin?
• 7599 high risk patients with recent TIA or
  ischemic stroke
   – Clopidogrel + aspirin 75 mg vs....
Clopidogrel + Aspirin?
• No difference in vascular events
• Increased life-threatening bleeding in the
  clopidogrel + asp...
European Stroke Prevention Study 2
                  (ESPS-2)
•       6602 patients with TIA or stroke within
        the ...
European Stroke Prevention Study 2
               (ESPS-2)
• Primary endpoints were stroke, death, or
  both

• Secondary ...
Benefit vs. Placebo
              for Endpoint of Stroke
• Aspirin 25 mg BID
   – ARR = 2.7%; NNT = 37
   – NNT/year = 74
...
Benefit vs. Aspirin
              for Endpoint of Stroke
• Combination aspirin + ER-dipyridamole
   – ARR = 3.0%; NNT = 33...
European Stroke Prevention Study 2
               (ESPS-2)
• Headache and gastrointestinal disturbances
  prompting stoppi...
PRoFESS
Effects of aspirin plus extended release
  dipyridamole versus clopidogrel and
 telmisartan on disability and cogn...
PRoFESS
• Patients ≥ 50 years old with an ischemic stroke in
  the last 90 days
• Patients 50-54 years old, or who present...
PRoFESS
• Randomized to:
   –   Aggrenox plus placebo
   –   Plavix plus placebo
   –   Aggrenox plus Telmisartan 80 mg da...
PRoFESS
• Looked at:
   –   Recurrent stroke
   –   Modified Rankin scores (disability measure)
   –   Barthel index (disa...
PRoFESS
• No difference in recurrent stroke

• No difference in stroke disabilty

• No difference in MMSE




 Lancet Neur...
Cost & Benefit Considerations for
                Recurrent Stroke
      Medication                             Cost per B...
Warfarin vs. Antiplatelets for
 Non-cardioembolic TIA/Stroke
• No evidence of warfarin superiority over
  antiplatelets fo...
Antiplatelet Take Home Points
• In patients with non-cardioembolic
  ischemic TIA/stroke, antiplatelet agents are
  recomm...
Antiplatelet Take Home Points
• Aspirin + ER-dipyridamole is more
  effective than aspirin alone
   – Class IIa, LOE B

• ...
Antiplatelet Take Home Points
• Addition of aspirin to clopidogrel increases
  the risk of hemorrhage and is not routinely...
Antiplatelet Take Home Points
• For patients that have an ischemic stroke
  while taking aspirin, there is no evidence
  t...
Cardiogenic TIA/Stroke
• Warfarin should be given for those with
  TIA or stroke if:
   – Persistent or paroxysmal atrial ...
Cardiogenic TIA/Stroke
• Warfarin should be given for those with
  TIA or stroke if:
   – Rheumatic mitral valve disease
 ...
Cardiogenic TIA/Stroke
• No solid data available on timing of
  anticoagulation after cardioembolic TIA or
  stroke
   – A...
Carotid Stenosis
• NASCET: North American Symptomatic
  Carotid Endarterectomy Trial

• Enrolled 659 patients with TIA or
...
North American Symptomatic Carotid
  Endarterectomy Trial (NASCET)
• All patients were less than age 80
• All patients und...
North American Symptomatic Carotid
  Endarterectomy Trial (NASCET)
• Stopped early due to great benefits of CEA:
   – 9% v...
North American Symptomatic Carotid
  Endarterectomy Trial (NASCET)
• Absolute risk reduction greater with
  increasing lev...
Lesser Levels of Stenosis after
           TIA/Stroke
• NASCET also looked at carotid stenoses
  <50% and 50-69% followed ...
50-69% Stenosis after TIA/Stroke
• 50-69% Stenoses (n=858) CEA vs. Medical
   – 15.7% vs. 22.2% of ipsilateral stroke
    ...
50-69% Stenosis after TIA/Stroke
• Surgery for all 50-69% symptomatic patients?
   – Women didn’t benefit as much with CEA...
NASCET + ECST Pooled Data
• Greater benefit for CEA if done earlier

• Time from last event to randomization to
  surgery ...
Carotid Evaluation




NNT            3.3       5.7   9   11




Lancet 2004;363:915-24
Carotid Take Home Points
• In the right patient, at the right time, the
  benefit is excellent!
   – Single-digit number n...
Carotid Take Home Points
• Better outcomes for CEA are seen with:
  – Higher (>70%) vs. lower (50-69%) degrees of
    sten...
Carotid Take Home Points
• When the ipsilateral stenosis is severe
  (>70%), CEA is recommended
   – (Class I, LOE A)




...
Carotid Take Home Points
• When the ipsilateral stenosis is moderate
  (50-69%), CEA is recommended depending
  on patient...
Carotid Take Home Points
• Order early carotid ultrasound in patients
  with stroke or TIA

• If the ultrasound shows grea...
A Tidbit About Diabetes
• PROactive: Effects of Pioglitazone in
  Patients With Type 2 Diabetes With or
  Without Previous...
A Tidbit About Diabetes
• In those with prior stroke, pioglitazone
  reduced fatal or nonfatal stroke
   – 5.6% vs 10.2%
 ...
A Tidbit About Diabetes
• HbA1C was 0.6 lower in the treatment group
  (P<0.0001)

• HDL and Triglycerides were also signi...
Take Home Points

• TIA/stroke is common, deadly, costly, and
  devastating
• First determine the mechanism, then target
 ...
Take Home Points

• The early risk of a significant stroke after a
  TIA or minor stroke is very high

• Don’t blow off TI...
Take Home Points

• Don’t acutely lower blood pressure after
  stroke

• Start thiazide plus ACE-I after stroke
  regardle...
Take Home Points

• Start a statin right away for patients with
  TIA/stroke, regardless of baseline LDL

• Strongly empha...
Take Home Points

• Start an antiplatelet agent after TIA/stroke

• Don’t combine clopidogrel + aspirin solely
  for strok...
Take Home Points

• Give warfarin to prevent another stroke if:
  – Atrial fibrillation
  – Acute MI with LV thrombus
  – ...
Take Home Points

• Order an early carotid ultrasound

• Order a CTA or MRA if stenosis is greater
  than 50% on ultrasoun...
Take Home Points

• Consult the Vascular Institute for all TIA
  and Stroke patients
• We are modeled after the Express Ca...
The Secondary Prevention Of Stroke For Linked In
The Secondary Prevention Of Stroke For Linked In
The Secondary Prevention Of Stroke For Linked In
The Secondary Prevention Of Stroke For Linked In
The Secondary Prevention Of Stroke For Linked In
The Secondary Prevention Of Stroke For Linked In
The Secondary Prevention Of Stroke For Linked In
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Transcript of "The Secondary Prevention Of Stroke For Linked In"

  1. 1. Now What??? The Secondary Prevention of Ischemic Stroke Jon Zlabek, MD, FACP
  2. 2. Learning Objectives • Review the evidence-based management and guidelines for patients with transient ischemic attack (TIA) and ischemic stroke • Emphasize the urgency of TIAs
  3. 3. The Six “Big Boys” • Hypertension • Hypercholesterolemia • Smoking • Antiplatelet Therapy • Cardioembolic TIA/Stroke • Carotid Stenosis
  4. 4. The Scope of the Problem • 795,000 people in the United States have a stroke each year – One every 40 seconds • 150,000 people in the United States die from a stroke each year – One every 4 minutes – Third leading cause of death www.strokeassociation.org
  5. 5. The Scope of the Problem • Good News! From 1994-2004 the stroke rate FELL by 24.2% and the number of stroke deaths FELL by 6.8% • Bad News! Thirty-day case fatality for ischemic stroke is 10-17% • 185,000 people have a recurrent stroke every year NEJM 2007;357:572-9 www.strokeassociation.org
  6. 6. Very High Risk Groups Increase in Risk of Stroke Site of Initial Event vs. General Population PAD 2-3 Times MI 3-4 Times Stroke 9 Times
  7. 7. BIG BUCK$ In 2010, for stroke-related expenses, Americans will pay an estimated 73.7 BILLION DOLLARS www.strokeassociation.org
  8. 8. Transient Ischemic Attack A brief episode of neurological dysfunction caused by a focal disturbance of brain or retinal ischemia with clinical symptoms typically lasting less than 1 hour, and without evidence of infarction. Stroke 2006;37:577-617
  9. 9. Stroke An episode of neurological dysfunction caused by a focal disturbance of brain ischemia with clinical symptoms lasting > 24 hours, OR imaging of an acute clinically relevant brain lesion with rapidly vanishing symptoms. Stroke 2006;37:577-617
  10. 10. TIA vs. Stroke • The distinction is becoming less important – Share common pathological mechanisms – Preventative approaches are similar Stroke 2006;37:577-617
  11. 11. TIA vs. Stroke • However, patients with TIA receive less aggressive diagnostic testing and treatment than stroke patients, despite a 5-year stroke risk over 30% • 200,000-500,000 patients have a TIA each year Dandapani B, unpublished data www.strokeassociation.org
  12. 12. Transient Ischemic Attack • About 15% of strokes are preceded by a TIA • The risk of a stroke after a TIA is very high, and most of the risk is very early – 9.9% at 2 days – 13.4% at 30 days – 17.3% at 90 days www.strokeassociation.org Stroke 2006;37:320-22 Arch Intern Med 2007;167(22)2417-22
  13. 13. Transient Ischemic Attack • Patients with TIA are very heterogenous in terms of symptoms, risk factors, and underlying pathology • However, you can predict who is headed for big trouble . . . Stroke 2006;37:320-22
  14. 14. Transient Ischemic Attack • Isolated sensory or visual symptoms are associated with lower risk of subsequent stroke JAMA 2000;284:2901-6 Lancet 2005;366:29-36
  15. 15. “ABCD” Score • “ABCD” Score • 7-day risk of CVA – Age > 60 (1 pt) – 6 = 31.4% – SBP > 140 and/or DBP >90 – 5 = 12.1% (1 pt) – 4 or less = 0.4% – Clinical features • Unilateral weakness (2 pts) – All patients with a • Speech problem (1 pt) stroke within one – Duration > 60 min (2 pts) week had scores 4 – Duration 10-59 min (1 pt) Lancet 2005;366:29-36
  16. 16. Express TIA Care Works! • EXPRESS study • Very thought-provoking study of patients with TIA or minor stroke • Several treatments are effective for secondary stroke prevention; assuming the effects are independent, appropriate use of these interventions should reduce the long term risk of recurrent stroke by 80-90% Lancet 2007;370:1432-42
  17. 17. Express TIA Care Works! • 91,000 patients in 9 primary care practices in Oxfordshire, UK • Lifelong medical records are kept (closed system) Lancet 2007;370:1432-42
  18. 18. Phase 1 – Baseline Cohort • Created an Express “TIA and Minor Stroke Clinic” • Physicians were asked to refer all patients with suspected TIA and minor stroke that didn’t need hospital admission • Kept the usual UK practice of: – Appointment-based (delays in referrals/contacting patients) – Didn’t start treatment; just made recommendations to the primary care provider Lancet 2007;370:1432-42
  19. 19. Phase 1 – Baseline Cohort • Primary physician faxed an appointment request after they saw an appropriate patient • The clinic contacted the patient at home by telephone • Made appointment for the next available weekday slot Lancet 2007;370:1432-42
  20. 20. Phase 1 – Baseline Cohort • Performed usual studies: – CT – EKG – Carotid Ultrasound – Transthoracic ECHO (when clinically indicated) • All studies were arranged during the following week Lancet 2007;370:1432-42
  21. 21. Phase 1 – Baseline Cohort • Recommendations faxed to primary care physician within 24 hours: – Aspirin 75 mg/day or Clopidogrel 75 mg/day (if aspirin contraindicated) • If “high early risk”, combined both for 30 days – Simvastatin 40 mg/day – Perindopril 4 mg/day +/- Indapamide 1.25 mg/day if SBP > 130 mmHg – Anticoagulation if indicated Lancet 2007;370:1432-42
  22. 22. Phase 1 – Baseline Cohort • No treatment/prescriptions were given to the patient • “Contact your primary care physician as soon as possible” Lancet 2007;370:1432-42
  23. 23. Phase 2 – Intervention Cohort • No appointments necessary • Physicians instructed to send all patients to the clinic the weekday afternoon after they first presented • Treatment initiated immediately – Both a time effect and a “get it done” effect Lancet 2007;370:1432-42
  24. 24. Phase 2 – Intervention Cohort • All patients given 300 mg of aspirin in clinic or a 300 mg loading dose of clopidogrel • Given a 30-day prescription for other medications: – Simvastatin – Perindopril +/- Indapamide – Warfarin if indicated – Clopidogrel if indicated Lancet 2007;370:1432-42
  25. 25. Results of Express Care • Phase 1 = 634 patients • Phase 2 = 644 patients • 95% of all referrals went to the Express Clinic Lancet 2007;370:1432-42
  26. 26. Results of Express Care • Delay to assessment in Express Clinic: – Phase 1 = 3 days – Phase 2 = less than 1 day (p<0.0001) – 1.7% vs 29.0% were seen in ≤ 6 hours (p<0.0001) • Delay to first prescription of treatment: – Phase 1 = 20 days (8-53 days) – Phase 2 = 1 day (0-3 days) (p<0.0001) Lancet 2007;370:1432-42
  27. 27. Results of Express Care • Statin used: – Phase 1 = 65% – Phase 2 = 84% (p<0.0001) • Aspirin + 30 days of clopidogrel: – Phase 1 = 10% – Phase 2 = 49% (p<0.0001) Lancet 2007;370:1432-42
  28. 28. Results of Express Care • On one or more blood pressure medications: – Phase 1 = 62% – Phase 2 = 83% (p<0.0001) • Carotid surgery within 7 days: – Phase 1 = 0% (n=17) – Phase 2 = 40% (n=15) (p=0.006) Lancet 2007;370:1432-42
  29. 29. Results of Express Care • 90-day risk of recurrent stroke – Phase 1 = 10.3% – Phase 2 = 2.1% (p=0.0001) – 80% reduction in risk • Those patients not referred to Express Care did not have any reduction of stroke • Early treatment did not increase risk of intracerebral or other bleeding Lancet 2007;370:1432-42
  30. 30. Stat TIA and Stroke Clinic
  31. 31. Now What??? • What can be done to combat this disease? – Very common – Deadly – Extremely costly – Devastating to patients and family
  32. 32. First Things First Do the best you can to determine the mechanism of the ischemic event
  33. 33. Mechanisms of TIA/Stroke • Large artery atherosclerotic • Cardioembolic • Small-vessel disease • Hemorrhagic • Undetermined cause • Other: – Dissections – Hypercoagulable states Stroke 2006;37:577-617
  34. 34. After you determine the mechanism, THEN . . .
  35. 35. Target the “Big Boys”
  36. 36. Hypertension THE MOST IMPORTANT RISK FACTOR FOR STROKE Stroke 2006;37:577-617
  37. 37. Hypertension • Affects 31% of U.S. adults (~50 million) • Control is poor: – 31% of patients with HTN are controlled – 53% of patients with HTN on therapy • Control in clinical trials is much better: – 66-70% Hypertension 2006;47:345-51 Stroke 2006;37:577-617
  38. 38. Hypertension • Stroke risk rises linearly from 115/75 mmHg • For every SBP elevation of 20 mmHg or DBP elevation of 10 mmHg, there is a doubling of stroke mortality JNC-7 NHLBI
  39. 39. Hypertension • About 60% of all strokes are attributable to hypertension – That’s 468,000 strokes per year in USA • Blood pressure control decreases initial stroke rate by 35-40% JNC-7 NHLBI
  40. 40. We Missed the News Flash! • Stroke & heart disease death rises linearly from 115/75 mmHg JNC-7 NHLBI
  41. 41. We Missed the News Flash!
  42. 42. We Missed the News Flash! • Stroke & heart disease death rises linearly from 115/75 mmHg • 141/88 should take on a new meaning with this tidbit – Get them off the bubble and into the “safe zone” JNC-7 NHLBI
  43. 43. Hypertension • During and immediately after a stroke, blood pressure may transiently elevate in a compensatory fashion • Acute reductions in blood pressure during the first 24 hours may be deleterious JNC-7 NHLBI Stroke 2003;34:1056-83
  44. 44. Hypertension • Blood pressure can fall by as much as 20/10 mmHg over the 10 days after stroke • Antihypertensive therapy can lead to an exaggerated reduction in cerebral blood flow acutely due to impaired autoregulation
  45. 45. Hypertension • Recommended only to acutely lower blood pressure if: – SBP >220 mmHg, or – DBP >120-140 mmHg • Use labetolol +/- nitroprusside to lower blood pressure by 10-15% JNC-7 NHLBI Stroke 2003;34:1056-83
  46. 46. Hypertension • After the acute event has passed, tight blood pressure control is essential – <130/80 mmHg if: • Diabetes or Chronic kidney disease • CAD or CAD equivalent (carotid disease, PAD, AAA, or 10 year risk ≥ 10%) – <120/80 if left ventricular dysfunction – <140/90 mmHg for the few others remaining JNC-7 NHLBI Circulation 2007;115:2761-2788
  47. 47. HTN Treatment after TIA/Stroke • PROGRESS: Perindopril Protection against Recurrent Stroke Study – Currently is the best data available in this group of patients – Another recent study (MOSES) had poor design and is fraught with controversy Lancet 2001;358:1033-41 Stroke 2005;36:1218-26
  48. 48. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) • 6105 patients with TIA or stroke within the past 5 years • Randomized to active treatment or placebo •Perindopril 4 mg daily PLUS •Double placebo Indapamide 2.5 mg daily (58%) OR OR •Single placebo •Perindopril 4 mg daily (42%) Lancet 2001;358:1033-41
  49. 49. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) • Primary outcome was fatal or non-fatal stroke • Duration of follow up 3.9 years • Prespecified subgroups of hypertensive and non-hypertensive patients at study entry – HTN defined as either SBP >160 mmHg or DBP >90 mmHg Lancet 2001;358:1033-41
  50. 50. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) • Baseline blood pressures: – Overall 147/86 mmHg – Hypertensive group 159/94 mmHg – Non-hypertensive group 136/79 mmHg Lancet 2001;358:1033-41
  51. 51. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) • Reduction in blood pressure vs. placebo – Active treatment group = 9.0/4.0 mmHg • Perindopril + Indapamide = 12.3/5.0 mmHg • Perindopril only = 4.9/2.8 mmHg – Hypertensive group = 9.5/3.9 mmHg – Non-hypertensive group = 8.8/4.2 mmHg Lancet 2001;358:1033-41
  52. 52. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) • Patients with primary endpoint of stroke: – Active treatment group = 10.1% – Placebo group = 13.8% • Absolute risk reduction 3.7% over 3.9 years • Number needed to treat = 27 Lancet 2001;358:1033-41
  53. 53. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) • In the active treatment group: – Fewer major vascular events – Fewer non-fatal vascular events – Fewer major coronary events – Fewer hospitalizations and if hospitalized, a shorter stay of 2.5 days Lancet 2001;358:1033-41
  54. 54. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) • Combination therapy vs. perindopril only – Perindopril + Indapamide better than placebo – Perindopril alone not better than placebo Lancet 2001;358:1033-41
  55. 55. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) • Hypertensive vs. Non-hypertensive groups – Reduction of stroke was the same – Reduction of major vascular events was the same • Patients without hypertension benefited as much as those with hypertension!!! – Similar to HOPE study (ramipril) Lancet 2001;358:1033-41
  56. 56. Hypertension Take Home Points • Don’t acutely lower blood pressure after stroke • Tight blood pressure control after the acute period is essential – Class I, LOE A
  57. 57. Hypertension Take Home Points • Start thiazide plus ACE-I after stroke – Class I, LOE A • Start blood pressure therapy regardless of presence of baseline hypertension – Class IIa, LOE B • After the acute event passes 115/75 mmHg is optimal
  58. 58. Hypercholesterolemia • Cholesterol studies to date mainly looked at patients from a cardiac point of view • Relative risk reduction for ischemic stroke in these studies ~ 20-30% Stroke 2002;35:1023 N Engl J Med 2005;352:1425 Ann Intern Med 1998;128:89 JAMA 1997;278:313
  59. 59. Hypercholesterolemia • Statins were the most studied agents • Niacin showed a reduction of cerebrovascular events in the Coronary Drug Project Stroke 2006;37:577-617 JAMA 1975;231:360-81
  60. 60. Hypercholesterolemia • SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels – 4731 patients with TIA/stroke within 1-6 months – No known coronary disease – LDL 100-190 mg/dl (mean 133 mg/dl) – Atorvastatin 80 mg/day vs placebo – Primary endpoint of fatal or non-fatal stroke NEJM 2006;355:549-59
  61. 61. SPARCL • Followed for 4.9 years • LDL levels at end of study – Atorvastatin group: 73 mg/dl – Placebo group: 129 mg/dl • Absolute risk reduction of stroke: 2.2% – P = 0.03 adjusted and 0.05 unadjusted NEJM 2006;355:549-59
  62. 62. SPARCL • Absolute risk reduction of major cardiovascular events: 3.5% – P = 0.002 • Small increase in hemorrhagic stroke in atorvastatin group • Overall mortality was the same in both groups NEJM 2006;355:549-59
  63. 63. Statins and Carotid Endarterectomy • Retrospective study looking at the association of statin use before CEA and outcomes – 1566 patients – Indication was for symptomatic disease in 42% – 42% received statin > 1 week before CEA J Vasc Surg 2005;42:829-36
  64. 64. Statins and Carotid Endarterectomy • Statin use was associated with: – Perioperative stroke rate 1.2% vs. 4.5% – Perioperative TIA rate 1.5% vs. 3.6% – All-cause mortality 0.3% vs. 2.1% – Length of stay 2 days vs. 3 days J Vasc Surg 2005;42:829-36
  65. 65. Statin Withdrawal After Stroke • Eighty-nine patients taking a statin who suffered an ischemic stroke • Randomized to atorvastatin 20 mg/day by mouth or NG tube vs. placebo for 3 days • On day 4, all patients were given atorvastatin 20 mg/day for 3 months Neurology 2007;69:904-10
  66. 66. Statin Withdrawal After Stroke • Measured: – Death/dependency – Early neurologic deterioration – Infarct volume Neurology 2007;69:904-10
  67. 67. Statin Withdrawal After Stroke • Statin withdrawal associated with: – 4.66-fold increased risk of death/dependency – 8.67-fold increased risk of early neurologic deterioration – 37.63 mL increase in mean infarct volume Neurology 2007;69:904-10
  68. 68. Hypercholesterolemia Take Home Point • Statin therapy should be started during hospitalization for patients with TIA/stroke, regardless of baseline LDL – Class I, LOE A if known atherosclerotic disease or elevated cholesterol levels – Class IIa, LOE B if no evidence of atherosclerosis and normal cholesterol levels Stroke 2002;35:1023 Stroke 2006;37:577-617
  69. 69. Smoking Is Bad • Major independent risk factor for ischemic stroke – Doubling of risk compared with nonsmokers • Risk of recurrent stroke decreases after quitting, and disappears after 5 years – Reduction in stroke-related hospitalizations Stroke 2006;37:577-617
  70. 70. Antiplatelet Therapy
  71. 71. Aspirin is Beneficial • United Kingdom TIA Trial – 2435 patients with TIA or minor stroke – Given 300 or 600 mg of aspirin or placebo – Duration of 4 years; endpoint of stroke – Both aspirin groups showed similar benefits – ARR = 2.2%; NNT = 45 – NNT/year = 180 J Neurol Neurosurg Psychiatry 1991;54:1044-54 Gundersen Lutheran Medical Journal 2005;3:62-5
  72. 72. Aspirin is Beneficial • Swedish Aspirin Low-Dose Trial – 1360 patients with ischemic stroke – Given 75 mg of aspirin or placebo – Duration of 32 months; endpoint of stroke – ARR = 2.6%; NNT = 38 – NNT/year = 101 Lancet 1991;338:1345-49 Gundersen Lutheran Medical Journal 2005;3:62-5
  73. 73. What about Ticlopidine? • Two major studies showed good results in TIA/stroke patients to prevent recurrence • CATS (ticlopidine vs. placebo) – Two years in duration – ARR = 6.6%; NNT = 15 – NNT/year = 30 Lancet 1989;1:1215-20 Gundersen Lutheran Medical Journal 2005;3:62-5
  74. 74. What about Ticlopidine? • TASS (1300 mg aspirin vs. ticlopidine) – 2.3 years in duration – ARR = 2.6%; NNT = 39 – NNT/year = 90 • Not used much due to adverse effects – Severe neutropenia in 0.8% – CBC every 2 weeks x 3 months NEJM 1989;321:501-7 Gundersen Lutheran Medical Journal 2005;3:62-5
  75. 75. Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) • 19,185 patients with recent myocardial infarction, stroke, or symptomatic PAD • Randomized to clopidogrel (Plavix) 75 mg/day or aspirin 325 mg/day for 3 years • Combined endpoint of fatal or nonfatal CVA, fatal or nonfatal MI, or vascular death Lancet 1996;348:1329-39
  76. 76. Lancet 1996;348:1329-39
  77. 77. Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) • Endpoint reached with aspirin 5.83% • Endpoint reached with clopidogrel 5.32% • ARR = 0.51% per year • NNT/year = 196 Lancet 1996;348:1329-39
  78. 78. Lancet 1996;348:1329-39
  79. 79. Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) • In the stroke subgroup (n=12,033 pt-yrs); to prevent another stroke: – ARR/year = 0.45% – Not significantly better than aspirin 325 mg – NNT is not applicable • No statistical significance Lancet 1996;348:1329-39
  80. 80. Clopidogrel + Aspirin? • MATCH: Management of Athero- Thrombosis with Clopidogrel in High-Risk Patients with Transient Ischemic Attack or Ischemic Stroke Lancet 2004;364:331-7
  81. 81. Clopidogrel + Aspirin? • 7599 high risk patients with recent TIA or ischemic stroke – Clopidogrel + aspirin 75 mg vs. – Clopidogrel alone • 18 month follow-up for stroke, MI, vascular death, or rehospitalization for ischemia Lancet 2004;364:331-7
  82. 82. Clopidogrel + Aspirin? • No difference in vascular events • Increased life-threatening bleeding in the clopidogrel + aspirin group – No difference in mortality however • No rationale for using this combination in this patient population Lancet 2004;364:331-7
  83. 83. European Stroke Prevention Study 2 (ESPS-2) • 6602 patients with TIA or stroke within the prior 3 months • Randomized to one of four arms: 1. Aspirin 25 mg BID 2. ER-dipyridamole 200 mg BID 3. Combination of aspirin + ER-dipyridamole (Aggrenox) 4. Placebo J Neurol Sci 1996;143:1-13
  84. 84. European Stroke Prevention Study 2 (ESPS-2) • Primary endpoints were stroke, death, or both • Secondary endpoints were TIA and vascular events • Followed for two years J Neurol Sci 1996;143:1-13
  85. 85. Benefit vs. Placebo for Endpoint of Stroke • Aspirin 25 mg BID – ARR = 2.7%; NNT = 37 – NNT/year = 74 • ER-dipyridamole 200 mg BID – ARR = 2.4%; NNT = 42; – NNT/year = 84 • Combination of these – ARR = 5.6%; NNT = 17.7 – NNT/year = 35 J Neurol Sci 1996;143:1-13
  86. 86. Benefit vs. Aspirin for Endpoint of Stroke • Combination aspirin + ER-dipyridamole – ARR = 3.0%; NNT = 33.6 – NNT/year = 67 • No significant effect on death rate alone • Less TIAs and vascular events in combination therapy group J Neurol Sci 1996;143:1-13
  87. 87. European Stroke Prevention Study 2 (ESPS-2) • Headache and gastrointestinal disturbances prompting stopping medication were more common in the combination group – 8.1% vs. 2.3% for headache – 7.0% vs. 3.6% for GI troubles • ESPRIT trial confirmed the superiority of aspirin + dipyridamole over aspirin alone J Neurol Sci 1996;143:1-13 Lancet 2006;367:1665-73
  88. 88. PRoFESS Effects of aspirin plus extended release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes trial
  89. 89. PRoFESS • Patients ≥ 50 years old with an ischemic stroke in the last 90 days • Patients 50-54 years old, or who presented 90-120 days after stroke if they had two of: – Diabetes – Hypertension – Smoker – Obesity – Prior vascular disease – High cholesterol – End organ vascular damage (retinopathy, LVH, microalbuminuria) Lancet Neurology 2008;7(10)
  90. 90. PRoFESS • Randomized to: – Aggrenox plus placebo – Plavix plus placebo – Aggrenox plus Telmisartan 80 mg daily – Plavix plus Telmisartan 80 mg daily Lancet Neurology 2008;7(10)
  91. 91. PRoFESS • Looked at: – Recurrent stroke – Modified Rankin scores (disability measure) – Barthel index (disability measure) – Mini-mental status examination Lancet Neurology 2008;7(10)
  92. 92. PRoFESS • No difference in recurrent stroke • No difference in stroke disabilty • No difference in MMSE Lancet Neurology 2008;7(10)
  93. 93. Cost & Benefit Considerations for Recurrent Stroke Medication Cost per Benefit over aspirin (Brand name) month* (NNT/year) Aspirin ~Dirt - Ticlopidine $101 90 (Ticlid) Clopidogrel $152 No benefit (Plavix) ER-dipyridamole/aspirin $173 67 (Aggrenox) *Price from www.drugstore.com; Accessed on March 10, 2009
  94. 94. Warfarin vs. Antiplatelets for Non-cardioembolic TIA/Stroke • No evidence of warfarin superiority over antiplatelets for non-cardioembolic stroke – SPIRIT – WARSS – WASID Stroke 2006;37:577-617
  95. 95. Antiplatelet Take Home Points • In patients with non-cardioembolic ischemic TIA/stroke, antiplatelet agents are recommended to reduce recurrent events – Class I, LOE A • Aspirin, aspirin + ER-dipyridamole, and clopidogrel are all acceptable initial options – Class IIa, LOE A Stroke 2006;37:577-617
  96. 96. Antiplatelet Take Home Points • Aspirin + ER-dipyridamole is more effective than aspirin alone – Class IIa, LOE B • Clopidogrel is not superior to aspirin in stroke patients, but is reasonable if aspirin allergic – Class IIa, LOE B Stroke 2006;37:577-617 Gundersen Lutheran Medical Journal 2005;3:62-5
  97. 97. Antiplatelet Take Home Points • Addition of aspirin to clopidogrel increases the risk of hemorrhage and is not routinely recommended for TIA/stroke patients – Class III, LOE A – (Class III means don’t do it!) Stroke 2006;37:577-617
  98. 98. Antiplatelet Take Home Points • For patients that have an ischemic stroke while taking aspirin, there is no evidence that increasing the dose is beneficial • No drug has been studied exclusively in patients who have had an event while taking aspirin Stroke 2006;37:577-617
  99. 99. Cardiogenic TIA/Stroke • Warfarin should be given for those with TIA or stroke if: – Persistent or paroxysmal atrial fibrillation • Risk of stroke is 5X higher • Class I, LOE A (Reduces stroke by ~ 60%) • If unable to take warfarin, give aspirin 325 mg/day – Class I, LOE A (Reduces stroke by ~ 20%) – Acute MI with left ventricular thrombus • Class IIa, LOE B Stroke 2006;37:577-617 Ann Intern Med 2007;146:857-67
  100. 100. Cardiogenic TIA/Stroke • Warfarin should be given for those with TIA or stroke if: – Rheumatic mitral valve disease • Add aspirin 81 mg daily if recurrent embolism • Class IIa, LOE C for both – Mechanical heart valves • Class I, LOE B • Add aspirin 81 mg daily if recurrent embolism – Class IIa, LOE B Stroke 2006;37:577-617
  101. 101. Cardiogenic TIA/Stroke • No solid data available on timing of anticoagulation after cardioembolic TIA or stroke – Aspirin 160 mg vs. full anticoagulation with LMWH for the first 14 days are equivalent – Initiate anticoagulation within 2 weeks, unless large infarct or uncontrolled hypertension Stroke 2006;37:577-617 Lancet 2000;355:1205-10
  102. 102. Carotid Stenosis • NASCET: North American Symptomatic Carotid Endarterectomy Trial • Enrolled 659 patients with TIA or nondisabling stroke with ipsilateral carotid stenosis 70-99% to CEA vs. standard treatment N Engl J Med 1991;325:445-53
  103. 103. North American Symptomatic Carotid Endarterectomy Trial (NASCET) • All patients were less than age 80 • All patients underwent cerebral angiogram • All patients received: – Up to 1300 mg daily of aspirin – Hypertension, cholesterol and/or diabetic therapy as indicated N Engl J Med 1991;325:445-53
  104. 104. North American Symptomatic Carotid Endarterectomy Trial (NASCET) • Stopped early due to great benefits of CEA: – 9% vs. 26% 2 year risk of ipsilateral stroke • ARR = 17%; NNT = 6 – 2.5% vs. 13.1% major or fatal ipsilateral stroke • ARR = 10.6%; NNT = 9 N Engl J Med 1991;325:445-53
  105. 105. North American Symptomatic Carotid Endarterectomy Trial (NASCET) • Absolute risk reduction greater with increasing levels of stenosis: – 90-99% = 26% NNT = 4 – 80-89% = 18% NNT = 6 – 70-79% = 12% NNT = 8 N Engl J Med 1991;325:445-53
  106. 106. Lesser Levels of Stenosis after TIA/Stroke • NASCET also looked at carotid stenoses <50% and 50-69% followed for 5 years: • <50% stenosis (n=1368) – No benefit N Engl J Med 1998;339:1415-25
  107. 107. 50-69% Stenosis after TIA/Stroke • 50-69% Stenoses (n=858) CEA vs. Medical – 15.7% vs. 22.2% of ipsilateral stroke • ARR = 6.5%; NNT = 15 – 33.2% vs. 43.3 % of stroke or death from any cause • ARR = 10.1%; NNT = 10 N Engl J Med 1998;339:1415-25
  108. 108. 50-69% Stenosis after TIA/Stroke • Surgery for all 50-69% symptomatic patients? – Women didn’t benefit as much with CEA • Due to low overall stroke rate in women • NNT for ipsilateral stroke was 67 • NNT for disabling stroke was 125 – TIA as entry symptom didn’t benefit as much • NNT for ipsilateral stroke was 27 • NNT for disabling stroke was 59 N Engl J Med 1998;339:1415-25
  109. 109. NASCET + ECST Pooled Data • Greater benefit for CEA if done earlier • Time from last event to randomization to surgery was studied, looking at ipsilateral stroke and stroke/death Lancet 2004;363:915-24
  110. 110. Carotid Evaluation NNT 3.3 5.7 9 11 Lancet 2004;363:915-24
  111. 111. Carotid Take Home Points • In the right patient, at the right time, the benefit is excellent! – Single-digit number needed to treat • Surgeons must have excellent outcomes data, as benefit quickly drops otherwise – Ours do!
  112. 112. Carotid Take Home Points • Better outcomes for CEA are seen with: – Higher (>70%) vs. lower (50-69%) degrees of stenosis – Men vs. Women – Stroke vs. TIA – CEA within 2 weeks of event vs. waiting – Surgeons with low rates of complications
  113. 113. Carotid Take Home Points • When the ipsilateral stenosis is severe (>70%), CEA is recommended – (Class I, LOE A) Stroke 2006;37:577-617
  114. 114. Carotid Take Home Points • When the ipsilateral stenosis is moderate (50-69%), CEA is recommended depending on patient-specific factors: – Age – Gender – Comorbidities – Severity of initial symptoms • (Class I, LOE A) Stroke 2006;37:577-617
  115. 115. Carotid Take Home Points • Order early carotid ultrasound in patients with stroke or TIA • If the ultrasound shows greater than 50% stenosis, order a confirmatory CT Angiogram or MRA
  116. 116. A Tidbit About Diabetes • PROactive: Effects of Pioglitazone in Patients With Type 2 Diabetes With or Without Previous Stroke • Prospective, double blind; 34.5 months • 5238 patients with history of macrovascular disease and diabetes • 984 patients with, and 4254 patients without prior stroke Stroke 2007;38:865-73
  117. 117. A Tidbit About Diabetes • In those with prior stroke, pioglitazone reduced fatal or nonfatal stroke – 5.6% vs 10.2% – ARR = 4.6% – NNT = 22 Stroke 2007;38:865-73
  118. 118. A Tidbit About Diabetes • HbA1C was 0.6 lower in the treatment group (P<0.0001) • HDL and Triglycerides were also significantly better in the treatment group (P<0.0001) • No benefit seen in those without a prior stroke – Risk of first stroke is lower than recurrent stroke Stroke 2007;38:865-73
  119. 119. Take Home Points • TIA/stroke is common, deadly, costly, and devastating • First determine the mechanism, then target the “Big Boys”
  120. 120. Take Home Points • The early risk of a significant stroke after a TIA or minor stroke is very high • Don’t blow off TIAs! Consider it a medical emergency!
  121. 121. Take Home Points • Don’t acutely lower blood pressure after stroke • Start thiazide plus ACE-I after stroke regardless of baseline hypertension • After the acute event passes 115/75 mmHg is optimal
  122. 122. Take Home Points • Start a statin right away for patients with TIA/stroke, regardless of baseline LDL • Strongly emphasize smoking cessation
  123. 123. Take Home Points • Start an antiplatelet agent after TIA/stroke • Don’t combine clopidogrel + aspirin solely for stroke prevention
  124. 124. Take Home Points • Give warfarin to prevent another stroke if: – Atrial fibrillation – Acute MI with LV thrombus – Rheumatic mitral valve disease – Mechanical heart valve
  125. 125. Take Home Points • Order an early carotid ultrasound • Order a CTA or MRA if stenosis is greater than 50% on ultrasound • Great benefit for CEA for stenoses >70% and in select patients with stenoses 50-69% – Best done within 2 weeks of event
  126. 126. Take Home Points • Consult the Vascular Institute for all TIA and Stroke patients • We are modeled after the Express Care Study – Showed 80% decrease in 90 day recurrent events vs no benefit for usual care – We will see them within 3 days
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