Stroke Prevention

1
Stroke Prevention
Whats new for 2006?
J. C. Martín del Campo. MD, FRCP. University
Health Network
2
Objectives

• To review current guidelines in secondary stroke
  prevention
• Antithrombic agents
• Antihypertensive agents
• Statins
• Anticoagulation
• Interventional therapies

3
AHA Classes and Levels of Evidence

• Class I Agreement the treatment is useful and
  effective
• Class II Conflicting evidence and/or a divergence
  of opinion about the usefulness/efficacy of a
  treatment.
• Class IIa Weight of evidence is in favor of the
  treatment.
• Class IIb Usefulness/efficacy is less well
  established by evidence
• Class III Evidence and/or general agreement that
  the treatment is not useful/effective and in
  some cases may be harmful.
• Levels of Evidence
• A Data derived from multiple randomized trials.
• B Data derived from a single randomized trial or
  nonrandomized studies.
• C Consensus opinion of experts.

4
Prognosis of Ischemic StrokeGerman Stroke Data
Bank
Follow-up after 90 days
14.70
18.60
Full Recovery or slight disabilities (mRS 0-2)
Moderate disabilities (mRS 3)
Severe disabilities (mRS 4-5)
Deceased
9.40
n 5,017
57.20
Grau AJ, et al. Stroke 2001322559-2566.
5
Short-term Prognosis after Emergency Department
Diagnosis of TIA
N 1707
30.0
25.0
Outcome events
20.0
15.0
12.7
10.5
10.0
Within90 days
5.0
2.6
2.6
5.3
Within48 hr
0.0
Stroke
CV event
Death
Recurrent TIA
Johnston SC, et al. JAMA 20002842901-2906.
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The Risk of Recurrent Stroke
Time Interval
Rate of Recurrence
30 days
3 - 8
25 - 40
5 year
2 year
25
gt70 carotid stenosis
Sacco, Neurology 45(suppl 1)S10, 1995
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Ischemic Stroke Mechanisms

• BLOOD VESSELS

• BLOOD

• HEART

8
Ischemic Stroke by Etiology
Adapted from the Stroke Databank
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Stroke Prevention - Non-cardioembolic ASA 2006
Secondary Stroke Recommendations

• For patients with noncardioembolic ischemic
  stroke or TIA, antiplatelet agents are
  recommended to reduce the risk of recurrent
  stroke and other cardiovascular events (Class I,
  Evidence A).

10
Antiplatelet Agents

• ASA
• dipyridamole
• ticlopidine
• clopidogrel
• GpIIb/IIIa antagonists
• combination therapy
• Aggrenox (dipyridamole ER ASA)
• clopidogrel ASA

11
Stroke Prevention - Non-cardioembolic ASA 2006
Secondary Stroke Recommendations

• Acceptable options for initial therapy (Class
  IIa, Level of Evidence A).
• aspirin (50-325 mg qd)
• the combination of aspirin and extended-release
  dipyridamole (25/200 mg bid)
• clopidogrel (75 mg qd)

12
Antiplatelets ASA 2006 Secondary Stroke
Recommendations

• Compared to aspirin alone, both the combination
  of aspirin and extended-release dipyridamole and
  clopidogrel are safe.
• The combination of aspirin and extended-release
  dipyridamole is suggested instead of aspirin
  alone. Class IIa, Level A
• Clopidogrel is suggested instead of aspirin alone
  based on direct comparison trials. Class IIb,
  Level B

13
Meta-analysis ASA vs. Placebo
ASA vs Placebo by Dose
Dose of ASA 1000-1300 mg 300 mg 50-75
mg Overall
RR 0.87 0.91 0.87 0.87
95 CI (0.76, 0.98) (0.76, 1.09) (0.78,
0.97) (0.81, 0.95)
Tijssen, 1998
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Secondary Stroke Prevention ASA 2006 Secondary
Stroke Recommendations

• For patients who have an ischemic cerebrovascular
  event while taking aspirin, there is no reliable
  evidence that increasing the dose of aspirin
  provides additional benefit.

15
Background

• after CIAO
• risk vascular event (stroke, MI, vascular death)
  4-11/year
• aspirin reduces risk by only 13

16
CAPRIE Cumulative Risk of Stroke, MI, or
Vascular Death
20
(Intention-to-Treat Analysis)
15
ASA
10
Clopidogrel
Cumulative risk ()
5
p .043
0
Time from randomization (months)
CAPRIE Steering Committee. Lancet 1996 348
13291339.
17
Secondary Stroke Prevention ASA 2006 Secondary
Stroke Recommendations

• The addition of aspirin to clopidogrel increases
  the risk of hemorrhage and is not routinely
  recommended for stroke or TIA patients. Class
  III, Level A
• For patients allergic to aspirin, clopidogrel is
  recommended. Class IIa, Level B

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MATCH Study Design
(n3,797)
Patients with recent IS or TIA at high risk
ASA 75mg o.d.
R
18 months double-blind treatment and follow-up
within 3 months
Placebo o.d.
(n3,802)
Day 0
18 month visit End of follow-up
Start of study drugs
3 month visit
6 month visit
12 month visit
R Randomization
1 month visit
All patients received clopidogrel 75 mg
background therapy
Diener et al. Lancet 2004 364 331-337.
19
MATCH Primary Outcome Results
Ischemic Stroke, Myocardial Infarction, Vascular
Death, Rehospitalization for acute ischemic event
0.20
Intention-to-Treat RRR 6.4 ARR 1.03
(p0.244)
Placebo
ASA
0.16
0.12
Cumulative event rate
0.08
On-Treatment Analysis RRR 9.5 ARR
1.61 (p0.101)
0.04
0.00
0
3
6
9
12
15
18
Months of follow-up
Diener et al. Lancet 2004 364 331-337.
20
Kaplan-Meier Curves for Cumulative Rates of
Primary Intracranial Hemorrhage in MATCH
4
Aspirin and clopidogrel Placebo and clopidogrel
3
Cumulative event rate ()
2
p0.029
1
0
0
3
6
9
12
15
18
Time since randomisation (month)
Patients at risk
Diener et al. Lancet 2004 364 (9431) 331337.
21
ASA Clopidogrel better
MATCH Sub-group Analysis
22
CHARISMA Study Design
Event-driven trial
Target N15,200
n7,600

• Patient Population
• High-risk symptomatic patients with 2 major, or 1
  major and 2 minor, or 3 minor risk factors
• Documented cerebrovascular disease
• Documented coronary artery disease
• Documented symptomatic PAD

Clopidogrel 75 mg ASA (75162 mg)
Placebo ASA (75162 mg)
n7,600
Up to 42 months

• Primary End Point
• First occurrence of nonfatal or fatal MI, or
  nonfatal or fatal stroke, or CV death

Bhatt DL et al. Am Heart J. 2004148263-268.
23
CHARISMA Primary End Point (CV Death, MI,
Stroke)
7.1 Relative risk reduction (95 CI -4.5 ,
17.5)
10
8
Placebo Aspirin
6
Clopidogrel Aspirin
4
P0.22 (not significant)
2
0
0
6
12
18
24
30
Months
No. at Risk
Clopidogrel
5299
7363
7510
7653
7802
2770
Placebo
5212
7316
7482
7644
7801
2753
Bhatt et al. N Engl J Med. 2006.354.
24
CHARISMA Safety Endpoint Overview
Bhatt et al. N Engl J Med. 2006.354.
25
ESPS-2 Results Stroke-Free Survival

100
95
ASA/ER-DP
Patients Without Stroke ()
90
ASA
ER-DP
85
Placebo
80
6
12
18
24
Time (months)
26
ESPS II Events, RRR, ARR, NNT
Endpoint all strokes

• Placebo ASA Dipyrid Comb
  Measure (50 mg/d) (400 mg/d) Therapy
• Events 250 206 211 157ARR 2.9 2.6 5.9RRR
  (p) 18 (.013) 16 (.039) 37 (lt.001)NNT 34 38 17
  
• ASA vs. ASA DI RRR 23.3, ARR 3.0, NNT
  33

Diener HC, et al. J Neurol Sci 1996 143 113.
27
Cardiac Safety of ER-DP in ESPS 2 Patients with
IHD at BaselineER-DP had no undesirable effect
on cardiac patients with stroke.

10.00
8.7
8.4
8.3
8.0
P lt 0.276
8.00
New Symptoms of Angina Pectoris During Follow-up
6.00
4.00
2.00
0.00
DP
No DP
ASA
No ASA
Diener HC, et al. Int J Clin Pract
200155162-163.
28
ESPS-2 a random high?

• 4 previous studies on ASAdip versus ASA after
  cerebral ischaemia
• ? RRR 3 (-22 - 22)
• discrepancy with ESPS-2 results
• ? RRR 22 (9 - 33)

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ESPRITEuropean/Australasian Stroke Prevention
after Reversible Ischemia Trial
Aspirin plus dipyridamole versus aspirin alone
after cerebral ischaemia of arterial origin
(ESPRIT) randomised controlled trial The ESPRIT
Study Group Lancet 2006 367 166573
30
ESPRIT
2739 patients
1363 ASA dipyridamole
1376 ASA

• TIA or ischemic stroke lt 6 mos.
• No atrial fibrillation
• mRS lt 3
• No planned endarterectomy
• No contraindications for ASA or dipyridamole

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ESPRIT
years
Hazard ratio (HR) 0.80 vascular death,
stroke, MI, major bleed 0.88 death 0.75
vascular death 0.67 major bleeding
Lancet 2006 367 166573
32
Rapid Development of Tolerance to
Dipyridamole-Associated Headaches
600
Results Headache episodes, being mostly mild
and transient, rapidly declined from 67 of the
volunteers on the first day of treatment to 3 on
the final days of treatment.
500
400
Intensity of headache
300
ER-DP
Placebo
200
n 33 Healthy volunteers
100
0
1
2
3
4
Onset on day
Theis JG, et al. Br J Clin Pharmacol
199948750-7555.
33
Conclusions

• ASADIP more effective than ASA in preventing new
  serious vascular events after CIAO
• Overall risk ratio ASADIP vs ASA
• 0.82 (95 CI 0.74-0.91)
• NNT/year 104 (55 - 1006)

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• Stroke prevention how many strokes can be
  prevented by risk factor control?

Heavy alcohol use
Atrial fibrillation
Cigarettes
Cholesterol
Hypertension
0
50,000
100,000
150,000
200,000
250,000
Number of strokes prevented
Gorelick PB. Arch Neurol 199552347-355
35
Blood Pressure and Risk of Stroke Mortality
10
Diastolic
Systolic
8
6
Risk of stroke mortality per
10,000 person-years
4
2
0
lt85
85-89
90-99
100
lt130
130-139
140-159
160
Blood pressure (mm Hg)
Multiple Risk Factor Intervention Trial (MRFIT)
n347,978 men. Neaton et al. In Laragh et al
(eds). Hypertension Pathophysiology, Diagnosis,
and Management.2 ed. NY Raven, 1995127
36
Stroke Prevention and Diastolic Blood Pressure
Decreasing DBP 5-6 mmHg for 5 years 42 RRR
in stroke
(Collins et al, Lancet 1990. 335827)
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Hypertension awareness, treatment and control
Wolf-Maier, K. Hypertension 20044310-17
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Targets
The current recommended target to reduce blood
pressure is lt 140 mm Hg systolic and lt 90 mmHg
diastolic in general. lt 130/80 mmHg in patients
with diabetes or chronic kidney disease.
Perspectives in Cardiology / March 2006
40
Each lifestyle modification is approximately
as effective in reducing blood pressure as one
prescribed medication.
JAMA 20032892083-2093.
41
V. Summary Treatment of Systolic-Diastolic
Hypertension without Other Compelling Indications
TARGET lt140/90 mmHg
Lifestyle modification therapy
Not indicated as first line therapy over 60
Dual Combination

• CONSIDER
• Nonadherence?
• Secondary HTN?
• Interfering drugs or lifestyle?
• White coat effect?

Triple or Quadruple Therapy
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V. Add-on therapy for Isolated Systolic
Hypertension without Other Compelling Indications
If partial response to monotherapy
Dual combination Combine agents from two adjacent
classes
Thiazide diuretic
ARB
Long-acting DHP CCB

• CONSIDER
• Nonadherence?
• Secondary HTN?
• Interfering drugs or lifestyle?
• White coat effect?

Triple therapy
If blood pressure is still not controlled, or
there are adverse effects, other classes of
antihypertensive drugs may be combined (such as
ACE inhibitors, alpha adrenergic blockers,
centrally acting agents, or nondihydropyridine
calcium channel blocker).
43
LIFE Losartan Was Superior to Atenolol in
Reducing the Risk of Fatal/Nonfatal Stroke
0.08
Atenolol
0.07
0.06
Losartan
0.05
0.04
Endpoint rate
0.03
0.02
Adjusted risk reduction 24.9 (p0.001)Unadjusted
risk reduction 25.8 (p0.0006)
0.01
0.00
0
180
360
540
720
900
1080
1260
1440
1620
1800
1980
Study day
Adapted from Dahlöf B et al Lancet
20023599951003.
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Rationale for selective AT1 blockade
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PPARs
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Key CHEP messages for the management of
hypertension

• Assess blood pressure at every visit
• Assess global cardiovascular risk in all
  hypertensive patients
• Lifestyle modifications are the cornerstone of
  both antihypertensive and antiatherosclerotic
  therapy
• Treat to target (lt140/90 mmHg lt130/80 mmHg in
  patients with diabetes or chronic kidney disease)
• Combinations of drugs are usually required to
  achieve blood pressure targets
• Focus on patient adherence to lifestyle
  modifications and antihypertensive therapy

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Blood Pressure ControlASA 2006 Secondary Stroke
Recommendations

• Antihypertensives are recommended beyond the
  hyperacute period (Class I, Evidence A).
• Benefit for those with w/o HTN (Class IIa,
  Evidence B)
• Target BP level and reduction are uncertain, but
  normal BP levels are lt120/80 by JNC-7 (Class
  IIa, Evidence B).
• Lifestyle modifications have been associated with
  BP reductions and should be included (Class IIb,
  Evidence C).
• Optimal drug regimen uncertain data support
  diuretics and the combination of diuretics and an
  ACEI (Class I, Evidence A).

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• Stroke prevention how many strokes can be
  prevented by risk factor control?

Heavy alcohol use
Atrial fibrillation
Cigarettes
Cholesterol
Hypertension
0
50,000
100,000
150,000
200,000
250,000
Number of strokes prevented
Gorelick PB. Arch Neurol 199552347-355
51
Observational Studies Association of Serum
Cholesterol and Stroke Rates

• Prospective StudiesCollaboration
• 45 prospectiveobservational cohorts
• Total of 450,000individuals
• Mean follow-up of16 years
• 13,397 strokesrecorded

1.2
1.0
Adjusted Stroke Rate
0.8
mmol/L
4.5
5.0
5.5
6.0
6.5
mg/dL
175
200
225
250
Total Cholesterol
Adjusted for study, age, sex, DBP, CAD hx, and
ethnicity
Adapted from Prospective Studies Collaboration.
Lancet. 19953461647-1653.
52
Correlation of LDL and stroke reduction
Amarenco et al. Lancet Neurology 2004 3271-8
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SPARCL Study Design
Atorvastatin 80 mg

• Patient population
• Stroke/TIA
• 16 months prior
• LDL 100190 mg/dL
• (2.64.9 mmol/L)
• Excludes prior CHD

4,732 patients
Placebo
5 years

• Primary endpoint
• Time to first fatal or nonfatal stroke

Sillesen H et al. Cerebrovasc Dis 200316389-395
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SPARCL results

• Time to stroke or TIA reduced by 23 (plt 0.001)
• Time to major coronary event reduced by 35
  (plt0.003)
• Decrease in revascularization procedures by 45
• Mean LDL 1.89 mmol/L

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Cholesterol Control ASA 2006 Secondary Stroke
Recommendations

• Those with elevated chol, CHD, or evidence of an
  atherosclerotic origin should be managed
  according to National Cholesterol Educational
  Program III (Class I, Evidence A).
• Statins are recommended with target LDL-C of lt2.5
  mmol/L and lt1.7 mmol/L for the very highrisk
  (Class I, Evidence A).
• Those with no pre-existing indications for
  statins (nl chol levels, no CHD, or no
  atherosclerosis), are reasonable to consider for
  statins to reduce the risk of vascular events
  (Class IIa, Evidence B).

57
Atrial Fibrillation ASA 2006 Secondary Stroke
Recommendations

• For patients with ischemic stroke or TIA with
  persistent or paroxysmal (intermittent) AF,
  anticoagulation with adjusted-dose warfarin
  (target INR 2.5, range 2.0 to 3.0) is recommended
  (Class I, Evidence A).
• For patients unable to take oral anticoagulants,
  aspirin 325 mg per day is recommended (Class I
  Evidence A).

Albers GW, et al. Chest (2001)119300S-320S.
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Estimate of Ipsilateral Stroke(5 year K. M.
Risks)
Stenosis
Patients
Events
Risk
NNT
p

Med
Surg
Med
Surg
Abs
Rel
70 99
331
328
26.1
12.9
13.2
51
8
0.00005
50 69
428
430
22.2
15.7
6.5
29
15
0.045
lt 50
690
678
18.7
14.9
3.8
20
26
0.16
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Atherosclerotic Carotid Stenosis
60
Carotid Endarterectomy ASA 2006 Secondary Stroke
Recommendations

• Ipsilateral severe (70 to 99) carotid stenosis,
  CEA is recommended (Class I, Evidence A).
• Ipsilateral moderate (50 to 69) carotid
  stenosis, CEA is recommended depending age,
  gender, comorbidities, and the severity of
  symptoms (Class I, Evidence A).
• Stenosis lt 50, there is no indication for CEA
  (Class III, Evidence A).
• Surgery within 2 weeks is suggested rather than
  delaying surgery (Class IIa, Evidence B).

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Carotid Angioplasty and Stenting
62
Carotid Angioplasty and Stenting ASA 2006
Secondary Stroke Recommendations

• CAS may be considered (Class IIb, Evidence B)
• if stenosis (gt70) difficult to access
  surgically,
• for medical conditions that greatly increase the
  risk for surgery, or
• when other circumstances exist such as
  radiation-induced stenosis or restenosis after
  CEA.
• CAS is reasonable when performed by operators
  with morbidity and mortality rates of 4 to 6
  (Class IIa, Evidence B).

63
Diabetes ASA 2006 Secondary Stroke
Recommendations

• More rigorous control of HTN and dyslipidemia
  should be considered in patients with DM.
• BP targets of 130/80 mm Hg (Class IIa, Evidence
  B). ACEIs and ARBs are recommended as
  first-choice medications for patients with DM
  (Class I, Evidence A).
• Glucose control to near normoglycemic levels to
  reduce microvascular complications (Class I,
  Evidence A) and possibly macrovascular
  complications.
• Hemoglobin A1c goal lt7 (Class IIa, Evidence B).

64
Post-menopausal Hormones ASA 2006 Secondary
Stroke Recommendations

• For women with ischemic stroke or TIA,
  postmenopausal hormone therapy (with estrogen
  with or without a progestin) is not recommended
  (Class III, Evidence A).

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Summary

• Multiple strategies to prevent secondary stroke
• Lifestyle modifications
• Antiplatelet or anticoagulant therapy
• Antihypertensives
• Statin therapy
• Endarterectomy/stenting
• Make sure your patients follow instructions.

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Thank You