Transcript Medication Management in Secondary Stroke Prevention

Medications for Secondary
Prevention of Ischemic Stroke
Alison Alleyne, PharmD
David Thompson Health Region
March 27, 2008
[email protected]
Outline
• Pathophysiology of Ischemic Stroke (IS)
– Preventing IS  preventing MI
•
•
•
•
Antiplatelets
Antithrombotics
Statins
ACEI & ARBS
Pathophysiology of IS
Terminology
• Transient Ischemic Attacks (TIA)
– brief episode of neurological dysfunction caused by a focal
disturbance of brain or retinal ischemia, with clinical
symptoms typically lasting less than 1 h, and without
evidence of infarction
• Precedes ischemic stroke in 60% of cases
• 35% of untreated patients will develop stroke within 5 years of TIA
• Stroke
– Stable – permanent no expected improvement/deterioration
– Improving – return of previously lost neurologic function
over days to weeks
– Progressing – continues to deteriorate following initial onset
of focal deficit
Pathophysiology of Stroke
Stroke
Primary Hemorrhage
(15%)
Intraparenchymal
Subarachnoid
Large Artery
Atherosclerotic
20%
Hypoperfusion
Arteriogenic embolic
Penetrating
artery disease
25%
“lacunar” (< 1.5 cm)
Cardiogenic embolism 20%
A fib
Valve disease
Ventricular thrombi
Others
Cryptogenic 30% (1 of the above, or other cause)
Other causes 5%
Prothrombotic states
Dissections
Arteritis
Migraine/vasospasm
Drug abuse
Others
Stroke Begets Stroke
80
70
60
50
Recurrent
Event (%)
40
Stroke
30
MI
20
10
0
Stroke
MI
First Event
Stroke 2002;33:901-6
Difference Between MI and IS
Myocardial Infarction
Type of Clot
Volume of Clot
Anatomy
Age of Patient
Safety
Outcomes
Platelet-rich thrombi on
plaque
Ischemic Stroke
Emboli from proximal
extracranial artery or 
- older, harder clots
Smaller diameter of main Extracranial internal
coronary arteries
carotid artery has large
diameter
Clots occur anywhere
Atherosclerosis
there is narrowing, due to contributes to only 20%
atherosclerosis
large artery IS; role in
other IS uncertain
Broader Variation
Most in > 65 y; higher
risk of ICH after
reperfusion
Lower risk of bleeding
Increased risk of
bleeding
Composite vs Single Endpoints in
IS Trials
• Can’t assume benefits of therapy from MI-prevention trials to ISprevention because anatomy is different
– primary prevention with ASA is of benefit for MI but not IS
• Composite endpoints allow a smaller sample size
•
– however, unless all components of a composite endpoint are affected in
the same direction and to a similar degree, their inclusion may not
provide the anticipated increase in statistical power.
Including “all cause mortality” is done to try to detect unexpected deleterious
effects of treatment, but only prevent other vascular-related deaths and allcause mortality at ½ the magnitude of stroke prevention (dilutes down
results)
For stroke/TIA patients, the single endpoint of stroke may be optimal
Albers G. Neurology 2000;54:1022-28
Clotting Cascade
A Clot is a Clot is a Clot?
Preventing a Second Event
• 26% of patients with stroke (46% of whom
had  1 prior event) and 27% of patients
with TIA (of whom 75% had  1 prior
event) are not taking preventive
(antiplatelet or antithrombotic) therapy.
Copernicus: The marketing Investment Strategy Group.
Patient Flow Analysis of Stroke/TIA Patients.
Waltham, Mass: Copernicus, 2006
Antiplatelet Therapy
Antiplatelet Agents
• ASA 50-325 mg daily
– start within 48h of symptom onset; begin with 160-325mg x 2
weeks
• Aggrenox® (ASA 50 mg and 200 mg
extended release (ER) dipyridamole) bid
• Clopidogrel 75 mg daily
• Ticlopidine 250 mg bid
BMJ 2002;324:71-86
ASA
•
•
•
IST: 19,000 pts received ASA 300 mg/day (within 48h; median 19h ) vs 2
different doses heparin x 2 weeks
– ASA had slightly fewer deaths (9% vs 9.4%), fewer recurrent IS (2.8%
vs 3.95% p = 0.03), no excess ICH (0.9% vs 0.8%), and trend toward 
death/dependency @ 6 mon (61.2% vs 63.5%)
CAST: 21,000 pts received ASA 160 mg/day vs PL within 48h of stroke and
for up to 4 weeks
– early mortality decreased (3.3% vs 3.9% p = 0.04)
– recurrent IS decreased (1.6% vs 2.1%, p=0.01) ;10% RRR
Antithrombotic Trialists’ Collaboration (ATC): meta-analysis of 287 studies,
involving 220,000 pts with previous MI, AMI, previous TIA/stroke, acute IS,
other high risk patients
– 25% decrease in stroke, MI, vascular death
•
Meta analysis of 23,00 patients from 21 RCT WITH PRIOR STROKE for
mean 29 mon= 22% reduction stroke, MI or vascular death (17.8 vs 21.4%
ARR 3.6%) NNT 40 in 3 y
ASA Dose for Stroke Prevention
Indication
Primary Prevention
Stroke in men 50+
Stroke in women 50+
Stroke with afib
Secondary Prevention
Stroke with hx TIA/IS
Stroke/death with hx IS
Lowest Effective Dose
(mg/day)
Unknown
> 100?
325
50
160
Am J Med 2006;119:198-202
Aggrenox: ESPS-2
Relative Risk Reduction%
40
37%*
35
30
23.1%**
25
16.3%***
18.1%***
20
15
10
5
0
ER DP/ASA
vs PL
ER DP vs PL
ASA vs PL
ER DP/ASA
vs ASA
ER DP, extended release dipyridamole; ASA, acetasalicylic acid; PL, placebo
*p < 0.001; ** p< 0.006; ***p< 0.05
J Neurol Sci. 1996 Nov;143(1-2):1-13
ESPRIT
• Randomized open label trial
• 2763 pts with TIA/IS within last 6 m (mRS < 3)
• Dipyridamole 200 mg bid + ASA 30-325 mg/d vs
ASA 30-325 mg daily x 3.5 y
– 83% used ER formulation
– 34% vs 13% discontinued trial
– median dose (75 mg in both gps) higher than daily
Aggrenox 50 mg
• Death + stroke + MI + major bleed = 13% vs 16%
(NNT 33 for 3.5 y or 100 pts for 1 year)
• meta-analysis confirms benefit of Aggrenox
Lancet 2006;367:1665-73
CAPRIE
• Clopidogrel 75 mg/day vs. ASA 325 mg/day in
noncardioembolic stroke (34%), MI (33%) or
Peripheral Artery Disease (34%)
• 19,185 patients over 1.91 years (range, 1-3 y)
•  ischemic stroke, MI or vascular death (5.32 vs.
5.83%; 8.7% RRR, p = 0.043)
• Initial stroke patients:
– 7.3% RRR for composite (CI - 5.7 to 18.7, p=0.26)
– 8% RRR for stroke only (CI -7 to 21, p=.28)
Lancet 1996;348:1329-39.
MATCH
• Clopidogrel + ASA vs. clopidogrel + PL
• 7599 pts with previous stroke/TIA
• Stroke, MI, vascular death or rehospitalization
for acute ischemia: 15.7% vs 16.7 %; RRR 6.4%
[95% CI -4.6 to 16.3, p= 0.24]
• Increased bleed in combination therapy group,
2.6% vs. 1.3%; ARI 1.3% [95% CI 0.6 to 1.9]
Lancet. 2004 Jul 24-30;364(9431):331-7
CHARISMA
• R, DB, PC clopidogrel 75 mg/d + ASA (75-162 mg/d) versus ASA +
placebo x median 28 months
• 15,603 high-risk asymptomatic patients, or symptomatic patients with
established CAD, CVD (~25%), or PAD.
– also received statins (77%), ACEI (64%), etc as per EBM
• MI, stroke or CV death occurred in 6.8% C+A vs 7.3% A (p=0.22)
– IS 1.7 vs 2.1%, RR 0.82, CI 0.66-1.04, p = 0.10
– all stroke (nonfatal) 1.9 vs 2.4%, RR 0.8 (CI 0.65-0.997, p = 0.05)
– when time to intervention was < 30days, trend towards increased
benefit
• trend of more severe bleeding in C+A (1.7 vs 1.3%, p=0.09)
• moderate bleeding higher in C+A 2.1 vs 1.3% (RR 1.62, CI 1.27-2.1,
p<0.0010
TIA or
Ischemic
Stroke
CAD
Present?
Yes
ASA
Clopidogrel
Recurrent
TIA/IS
ASA
No
Clopidogrel
ASA + ER-DP
Recurrent
TIA/IS
Recurrent
TIA/IS
Recurrent
TIA/IS
Clopidogrel
Or ASA
& Clopidogrel
No change,
or Assess Risk
vs Benefit of
combination Tx
No change* or  ASA or Clopidogrel
or ASA & ER-DP
Recurrent
TIA/IS
ASA & ER-DP
or Clopidogrel*
Clopidogrel or
ASA & ER-DP*?
* assess compliance, adverse effects, drug interactions,etc
Anticoagulants in Non-Cardioembolic IS
No benefit, and increased risk of bleeding
– SPIRIT: warfarin (INR 3-4.5) vs ASA 30 mg/day
• stopped early due to 2.3 fold increase in death
• Bleeding increased 1.43 fold per 0.5 increase in INR
– WARSS: - warfarin (INR1.2 -2.8) vs ASA 325 mg/day
• no difference in prevention of early recurrent IS or death
– ESPRIT (warfarin vs ASA arm)
• no superiority of warfarin
– WASID: warfarin (INR 2-3) vs ASA 1300 mg/day
• stopped early, due to increased mortality (4.3% vs 9.7%, p=0.02)
and major hemorrhage (3.2% vs 8.3%, p= 0.01) with warfarin
• NSD in patients with atherosclerotic intracranial arterial stenosis
Anticoagulation in Nonvalvular
Atrial Fibrillation
When to Use Anticoagulation
• Cardioembolic stroke
– persistent or paroxysmal atrial fibrillation (INR
2-3)
– acute MI with left ventricular mural thrombus
(INR 2-3)
– rheumatic mitral valve disease (INR 2-3)
– mechanical prosthetic valve (INR 2.5-3.5)
• Cerebral venous sinus thrombosis
• Arterial dissections
• Hypercoagulable states
Cardioembolic Stroke
The left atrial appendage of a woman with atrial fibrillation who suffered
a thromboembolic event. Organized 5mm thrombi are apparent. A 5mm thrombus
can completely occlude the middle cerebral artery.
Warfarin vs. Placebo in AFib
N
Target INR ARR (%/yr)
RRR (%)
AFASAK
671
2.8-4.2
2.6
54
SPAF-1
421
2-4.5
4.7
60
BAATAF
420
1.5-2.7
2.4
78
CAFA
378
2-3
1.2
33
SPINAF
571
1.4-2.8
3.3
70
EAFT
439
2.5-4
8.4
68
6 Trials
2900
1o Prx 2.7
2o Prx 8.4
64 (05% CI
49-74)
Hart RG. Ann Intern Med 2007;146:857-67
Antiplatelet vs Placebo in Afib
N
Dose
ARR (%/yr)
RRR (%)
AFASAK
672
75 mg/day
0.9
17
SPAF-1
1120
325 mg/day
2.5
44
EAFT
782
300 mg/day
1.9
11
ESPS II
211
50 mg/day
6.9
29
UK-TIA
28
36
2834
300 mg/day
1200 mg/day
50-1200 mg/day
0.9
0.7
1o Prx 1.9
2 o Prx 2.5
17
14
22
(95% CI 2 to 39)
5 Trials
Hart RG. Ann Intern Med 2007;146:857-67
Warfarin vs ASA in AF
N
AFASAK I (89, 90)
INR Target ARR (%/yr)
RRR (%)
671
2.8-4.2
1.7
45
SPAF II (94)
( 75 yr)
715
2-4.5
0.2
10
SPAF II (94)
(> 75 yr)
385
2-4.5
0.5
10
EAFT (93)
455
2.5-4
7
67
AFASAK II (98)
339
2-3
-0.6
-23
PATAF (99)
272
2.5-3.5
0.3
20
Vemmos (06)
31
1.6-2.5
40
100
Chinese ATAFS (06)
704
2-3
1.2
43
WASOP (07)
75
2-3
NC
NC
1o Prx 0.7
2 o Prx 7
38 (18 to 52)
8 Trials
3647
Hart RG. Ann Intern Med 2007;146:857-67
ACTIVE W
• 6700 pts with afib and at least 1 risk factor
for stroke
• warfarin (INR 2-3) vs. ASA 75-100 mg/d +
clopidogrel 75 mg/d
• Primary endpoint: stroke, systemic
embolus, MI or vascular death
• stopped early, due to superiority of
warfarin group
Safety Outcomes
N
ICH
Events, n
RRR (95% CI)
ARR, %/yr
Major extracranial
hemorrhage, n
RRR (95% CI)
ARR, %/yr
All-cause Mortality
Deaths, n
RRR (95% CI)
ARR, %/yr
Warfarin vs Ctl/PL
ASA vs CTL
Warfarin vs ASA
2900
3762
3647
6 vs. 3
NC
NC
8 vs. 4
NC
NC
20 vs. 7
-128 (-300 to –4)
-0.2
31 vs. 17
-66 (-235 to 18)
-0.3
16 vs. 15
2 (-98 to 52)
-0.2
184 vs. 204
40 vs. 22
-70 (-234 to 14)
-0.2
110 vs. 143
26 (3 to 43)
1.6
14 (-7 to 31)
0.5
117 vs. 128
9 (-19 to 30)
0.5
Hart RG. Ann Intern Med 2007;146:857-67
Anticoagulation
• Warfarin in nonvalvular afib decreases
stroke recurrence from 12% to 4%
annually, whereas ASA only decreases
risk to 10%.
– NNT 11 to prevent 1 stroke in 1 year
• Benefit outweighs risk of bleed (even in
elderly:
– Extracranial bleed: 2.3% per year
– ICH in ≥ 60 years: 0.3-1.7%
Lancet 1993;342:1255-62
ACC/AHA/ESC Afib Guidelines
Prevention must consider:
• risk of stroke
• bleed risk
• ability to safely sustain anticoagulation
• patient preference
Circulation 2006;114:e257-e354
CHADS2 Score
C = Congestive HF (EF<35%) (1 point)
H = HT (1 point)
A = Age > 75 y (1 point)
D = Diabetes (1 point)
S = previous Stroke/TIA (2 points)
0 points = ASA 75-325 mg daily
1 point = ASA 75-325 mg daily or warfarin
(INR target 2-3)
 2 points = warfarin (INR target 2-3)
Risk Assessment
High
Intermediate
Low
AFI
> 65y, Hx of HT, CAD or DM
< 65y; No high risk
features
SPAF
Women > 75 y,
SBP > 160 mmHg,
LV dysfunction
Score 3-6
No hx HT; No high risk
features
CHADS2
Framingham
ACCP
NICE/
Birmingham
ACC/AHA/
ESC
Score 1-2
Score 0
Weighted Score: points for being older (up to 9), sex (F=6, m=0),  BP (up to 3),
DM (6). Total score (max 31) predicted 5y stroke risk: 0-7 = low risk; 8-13 =
intermediate risk, 14-31 = high risk
Prior IS/TIA/ embolism; > 75y; Age 65-75y, with no
< 65 y with no RF
mod-severe LV function w/wo
other RF
HF; HT, DM
Age < 65 with no hx
Prior IS/TIA/embolism;  75y w/ Age  65 with no high
embolism, HT, DM or
HT, DM or vascular disease;
RF; age < 75 with HT,
valve disease or HF; impaired
DM or vascular disease other RF
LV function
Prior IS/TIA/embolism; valve
AF (no other RF)
Age  75; HT; HF;
disease; more than 1 of:  75,
impaired LV function;
HT, HF, impaired LV function;
DM
or DM
Antithrombotic Therapy for
Patients with AFib
Risk Category
No Risk Factors
1 Moderate RF
Any High RF or >1
Moderate RF
Recommended Therapy
ASA 81-325 mg/day
ASA 81-325 mg/day or Warfarin (INR 2-3)
Warfarin (INR 2-3)
Weaker RF
Moderate RF
High HF
Female
Age 65-74 y
CAD
thyrotoxicosis
 75 y
HT
HF
EF< 35%
DM
PreviousTIA, stroke,
embolism
Circulation 2006;114:e257-e354
Afib--Other Recommendations
• If no mechanical valve, can hold treatment for up to
1 week for procedures
• Must regularly re-evaluate need for anticoagulation
• If pt is > 75 y or has moderate RF but you can’t
safely get pt to INR 2-3, consider warfarin
targetting INR 1.6-2
• If < 60 years with lone AF, risk/benefit of ASA for
primary prevention not established
• If patient with afib strokes on warfarin, consider
increasing intensity, rather than adding antiplatelet
Suggestions for Anticoagulation in Patients
with AF who present with AIS or TIA
• Normalize BP before starting anticoagulation
• In patients with AF and AIS
– do imaging (CT or MRI) to exclude hemorrhage
• if no cerebral hemorrhage, begin anticoagulation after 2
weeks (use ASA in the interim)
• if cerebral hemorrhage, do not anticoagulate
• delay therapy if large cerebral infarction
• In patients with AF and TIA
– do imaging (CT or MRI) to exclude hemorrhage
• if no cerebral hemorrhage, begin anticoagulation as soon as
possible
Lip GYH. Lancet Neurol 2007;6:981-93
Paciaroni M. Stroke 2007;38:423-30
Antiplatelets and Anticoagulants--Summary
Stroke Etiology
Treatment Strategy
Cardioembolic Stroke (CS)
Warfarin, INR 2-3
Non-CS or CS with
1. ASA or ASA/ER-DP
contraindication to anticoagulation 2. Clopidogrel
Cryptogenic stroke
3. Ticlopidine
Non-CS with PVD
Clopidogrel
Recurrent IS despite antiplatelet
monotherapy
Alternative antiplatelet or
warfarin*
Carotid or vertebral artery
dissection
Warfarin
Hypercoagulability
Warfarin
Koennecke. CNS Drugs 2004;18:221-41
Statins
SPARCL
• 4731 patients with TIA or stroke (excluding cardioembolic stroke)
within 1-6 months
– LDL 2.6-4.9, no CAD
– did not already have indication for statin???
– Atorvastatin 80 mg/d vs PL
• Primary Endpoint endpt--first nonfatal or fatal stroke
Results
• median follow up 4.9y
• median LDL 1.9 vs 3.3
N Engl J Med 2006;355:549-59
SPARCL: Main results
Type of stroke
Any
Fatal
Nonfatal
Ischemic
Hemorrhagic
Hazard ratio (95% CI)
with atorvastatin
0.84 (0.71-0.99)
0.57 (0.35-0.95)
0.87 (0.73-1.03)
0.78 (0.66-0.94)
1.66 (1.08-2.55)
N Engl J Med 2006;355:549-59.
Meta-Analysis of Stain Therapy for Stroke Prevention
All- stroke prevention:
16% RRR
(RR 0.84, CI 0.79-0.91)
O’Regan C. Am J Med 2008;121;24-33
Thiazide Diuretics
Angiotensin Conventing
Enzyme Inhibitors (ACEIs)
Angiotensin Receptor
Blockers (ARBs)
ALLHAT Health Effects of Diuretics
Low-dose thiazide-type diuretic-based
treatment in large clinical trials has been
shown to reduce the risks of:
Event reduction %
Stroke
34
Heart failure
42
CHD
28
CVD mortality
24
Total mortality
10
Psaty et al., JAMA 1997;277:739-45
JAMA 2002;288:2981-2997
ACEI-- HOPE STUDY
Outcome
ARR %
Relative Risk [RRR %]
(95% CI)
Combined outcome:
MI, stroke, CV death
3.8
0.78 [22%] (0.70-0.86)
All stroke
1.5
0.68 [32%] (0.56-0.84)
Fatal stroke
0.5
0.39 [61%] (0.22-0.67)
Non-fatal stroke
0.9
0.76 [24%] (0.61-0.94)
Ischemic stroke
1.2
0.64 [36%] (0.50-0.82)
N Engl J Med 2000;342:145-53
PROGRESS
Lancet. 2001 Sep 29;358(9287):1033-41
Stroke 2005;36:2164-9
ARBS for Secondary Stroke Prevention
LIFE
Lancet. 2002;359(9311):1004-10
LIFE. Lancet 2002;359:1004-10
ACCESS
•
•
•
motor deficit, no bleed, and HT (
200/110 6-24h after admission or
 180/105 24-36h after admission)
x 7 days….after which
candesartan could be added to
the PL group is required for BP
management (problem--broke
blinding, but evaluators still
binded)
stopped early; mortality and
vascular events decreased with C
NSD in BP at study onset, first 7
days, and subsequent 12 months
Stroke. 34(7):1699-703, 2003 Jul.
MOSES
• Morbidity and Mortality after Stroke, Eprosartan
compared with nitrendipine for Secondary
prevention
• 1405 high risk patients
–
–
–
–
hypertension
cerebral event within last 24 months
eprosartan 600 mg daily vs nitrendipine 10 mg daily
mean follow up 2.5 years
• primary endpoint: death + cardiovascular event
+ cerebrovascular event
Schrader J. Stroke 2005;36:1218-26
Schrader J. Stroke 2005;36:1218-26
MOSES-Results
Schrader J. Stroke 2005;36:1218-26
PROFESS
Future Research
• ONTARGET and others
– Ongoing Telmisartan Alone in Combination
with Ramipril Global Endpoint Trial
• Combination therapy for neuro- and
vascular protection
– anesthesia
– thrombolytic
– blood brain barrier integrity protector
– neuroprotector
– neuro antiinflammatory
J Neurochem 2007;103:1302-1309
Conclusions
• Ischemic stroke is a prevalent disease, with
devastating sequelae.
• Stroke begets stroke.
• Therapies for secondary stroke prevention have
expanded in recent years, and are often
determined based on concomittant diseases.
• Improvements in study methodology will help
clarify optimal therapies for stroke (including
stroke subtypes), and differentiate them from
therapies for MI.
Web Sites
NINDS. The Brain Attack Coalition.
http://www.Stroke-site.org
American Heart Association
http://www.americanheart.org
National Stroke Association http://www.stroke.org
European Neurological Society, the European
Federation of Neurological Society, and he
European Stroke Council. The European Stroke
Initiative http://www.EUSI-stroke.com