Anne E. ODuffy, MD

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Stroke Prevention -- Are We Making Progress?

• Anne E. ODuffy, MD
• Assistant Professor of Neurology
• Stroke Division
• Vanderbilt University Medical Center
• February 7, 2005

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Stroke Mortality
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Stroke Subtypes
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Stroke MortalityHankey,GJ Stroke 2000312080-86
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• We (Still) Must Focus on PREVENTION!

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Carotid Procedures vs Surgery

• SAPPHIRE Stenting and Angioplasty with
  Protection in Patients at High Risk for
  Endarterectomy, 1st randomized trial of stenting
  plus embolic protection with CEA
• 723 pts, symptomatic 50, asymptomatic 80 plus
  one co-morbidity (CHF, recent MI, CABG,
  contralateral occlusion, age 80)
• 307 randomized, 409 enrolled in stent registry, 7
  refused by interventionalist, surgical registry
• Both ASA, Plavix x 2wks in stent pts, heparin
  during procedure

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Angioguard
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SAPPHIRE Results

• Device success 91.2
• 30-day combined endpoints death, stroke, MI 5.8
  stent group vs 12.6 surgical pts
• Stroke 3.8 vs 5.3
• MI 2.6 vs 7.3
• Death 0.6 vs 2.0
• Reported by P. Fayad, ASA, Phoenix 2/03 and AAN,
  Honolulu, 2003
• We require longer-term follow-up for durability,
  proof of efficacy in lower-risk pts.,
  demonstration of safety in the community

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Ongoing Studies

• SAPPHIRE 1 year results
• CREST (NINDS), 9000 pts.
• CAVATAS II, 2000 pts.
• SPACE, (Germany)1900 pts.
• EVA, (France),900 pts.

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Stroke Risk and BP
UK-TIA trial BMJ 313 (1996), p. 147
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Hypertension

• Commonest stroke risk factor, 50 million
  Americans, undertreated
• HOPE suggested that ACE-I ramipril reduced
  stroke, MI, vascular death by 22 greater than
  placebo (32 reduction in stroke)
• Yusef,et al NEJM 2000 342 145-153
• LIFE 1 stroke prevention trial in high-risk pts
  losartin better than atenolol
• Dahlof et al Lancet 2002 359 995-1003

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Hypertension

• PROGRESS 2 stroke prevention in 6105 patients w/
  hx stroke/TIA (irregardless of history of HTN)
  perindopril w/ or w/o indapamide vs placebo found
  28 reduction in stroke in active tx arm and
  43 reduction w/combination therapy
• Lancet, Vol. 358 September 29,2001

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PROGRESS Results
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PROGRESS Results
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PROGRESS Results
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Hypertension

• ALLHAT trial 33,000 pts w/ HTN and 1 other
  vascular risk factor tx w/ chlorthalidone ,
  lisinopril or amlodipine
• No differences in 1 outcome measures of fatal
  or non-fatal MI, chlorthalidone was better than
  lisinopril in preventing stroke and combined
  vascular endpoint of stroke, MI, and PVD
• Nearly 30 pts were black and thus more likely to
  do better w/ diuretics
• JAMA, December 18,2002Vol 288,no 23,2981-97

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Hypertension

• Specific BP agent may be less important than BP
  lowering for stroke prevention
• The Seventh Report of the Joint National
  Committee on Prevention, Detection, Evaluation,
  and Treatment of High Blood PressureThe JNC 7
  Report
• JAMA, May 21, 2003Vol 289, No. 19, 2560-72

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Lipid Lowering

• Statins very effective in stroke reduction in pts
  w/ CAD
• 4S, CARE, LIPID trials shown 19- 28 reduction
  in stroke outcomes in CAD pts
• SPARCL (Stroke Prevention by Aggressive Reduction
  in Cholesterol Levels) 2 stroke prevention,
  ongoing

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Womens Estrogen for Stroke Trial (WEST)

• Randomized, double-blind, placebo-controlled
  trial of estrogen therapy in 664 postmenopausal
  women who had recently had an ischemic stroke or
  TIA, mean follow-up of 2.8 years
• Results Estrogen therapy did not reduce the
  risk of death alone, or of nonfatal stroke

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WEST Results
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Womens Health Initiative (WHI)

• Defining the risks and benefits of strategies
  that could potentially reduce the incidence of
  heart disease, breast and colorectal cancer, and
  fractures in postmenopausal women
• 16,608 women, primary outcome was CHD
• Study stopped early after mean follow-up of 5.2
  years based on health risks that exceeded
  benefits
• JAMA.2002288321-333

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WHI Results for Stroke
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WHI Results

• HRs for CHD 1.29, breast cancer 1.26, stroke
  1.41, PE 2.13, colorectal ca 0.63, endometrial ca
  0.83, hip fractures 0.66, other deaths 0.92
• Absolute excess risks per 10,000 person-yrs 7
  more CHD events, 8 more strokes (4800 total
  strokes/yr est.), 8 more PEs, 8 more invasive
  breast cas
• Absolute risk reductions 6 fewer colorectal
  cas, 5 fewer hip fractures

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Blood Clot
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Rate vs. Rhythm?

• AFFIRMAtrial Fibrillation Follow-up
  Investigation of Rhythm Management
• 4000 high-risk patients w/afib
• Rhythm control just as likely to suffer ischemic
  stroke over 3.5 yrs. as those who receive rate
  control alone
• Warfarin reduced stroke by 68
• Presented at AAN, Honolulu, HI, PI Sherman,DG,

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Are Warfarins Days Numbered?

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Ongoing,Recent Studies of Anti-Platelet Agents
Stroke Prevention

• MATCH Plavix vs. ASA Plavix in high risk
  patients w/ stroke, TIA
• CHARISMA ASA vs. ASA Plavix, 15,000
  pts.(combined vascular endpoints)
• PRoFESS Study
• SPS3

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MATCH

• Management of ATherothrombosis with Clopidogrel
  in High-risk patients with recent TIA or ischemic
  stroke
• Plavix aspirin vs Plavix alone in high-risk
  stroke/ TIA patients (MI, DM, PVD)
• 7599 pts, 500 centers, 28 countries
• 15.7 of patients taking clopidogrel ASA had a
  further ischemic event vs 16.73 of patients
  taking clopidogrel placebo (p.244)

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MATCH Results
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MATCH Results

• Life threatening bleeding 2.6 vs 1.3
• P
• Raises serious concern about use of combination
  anti-platelet agents in stroke patients
• May affect ongoing studies
• Do we need to think beyond the platelet ?

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PRoFESS

• Prevention Regimen For Effectively avoiding
  Second Strokes
• 2 x 2 factorial design Aggrenox vs. clopidogrel
  with or w/out Micardis (telmesartan)
• N 15,500
• Adults, 55 yrs, ischemic stroke within 90 days
• Enrollment period 2 yrs, study duration 4 yrs.

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SPS3

• Secondary Prevention of Small Subcortical Strokes
• Hypertension causes primarily brain disease
  (stroke, cognitive decline, unsightly
  leukoariosis on MRI)
• Benefits of modest BP lowering after stroke
  comparable to antiplatelet agents
• Lowering BP is more important than the specific
  agent(s) used to do it

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SPS3

• Multicenter phase III randomized 2x2 controlled
  trial
• 2500 patients
• 325 mg aspirin vs aspirin clopidogrel
• Targeted BP control usual (systolic 130-149) vs.
  aggressive (systolic
• Primary efficacy outcome recurrent stroke during
  mean follow-up 3 yrs.
• Secondary outcomes cognitive status, major
  vascular events, death

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A strategy to reduce cardiovascular disease by
more than 80

• Simultaneously reduce four CV risk factors (LDL
  cholesterol, BP, homocysteine, platelet function)
• 10mg atorvastatin or 40mg simvastatin, 3 BP meds
  at half-strength (thiazide, beta-blocker, ACE-I),
  0.8mg folic acid, 75mg aspirin
• 1/3 people would benefit from the Polypill,
  gaining average of 11 yrs free from IHD or stroke
• NJ Wald, MR Law, BMJ Vol 326 28 June, 2003

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Conclusions

• While acute stroke interventions capture our
  imagination, the most significant impact on
  reducing the devastation of stroke remains its
  prevention.
• The data is convincing, and yet has not been
  fully disseminated to physicians and patients.

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