Medications for Secondary Prevention of Ischemic Stroke

Alison Alleyne, PharmD

David Thompson Health Region

March 27, 2008

aalleyne@dthr.ab.ca

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

Large Artery Atherosclerotic

20%Hypoperfusion

Arteriogenic embolic

Penetrating artery disease

25%“lacunar” (< 1.5 cm)

Cardiogenic embolism 20% A fib

Valve diseaseVentricular thrombi

Others

Primary Hemorrhage (15%)

IntraparenchymalSubarachnoid

Other causes 5%Prothrombotic states

DissectionsArteritis

Migraine/vasospasmDrug abuse

Others

Cryptogenic 30% (1 of the above, or other cause)

Stroke Begets Stroke

0

10

20

30

40

50

60

70

80

Recurrent Event (%)

Stroke MI

First Event

Stroke

MI

Stroke 2002;33:901-6

Difference Between MI and IS

Myocardial Infarction Ischemic Stroke

Type of Clot Platelet-rich thrombi onplaque

Emboli from proximalextracranial artery or - older, harder clots

Volume of Clot Smaller diameter of maincoronary arteries

Extracranial internalcarotid artery has largediameter

Anatomy Clots occur anywherethere is narrowing, due toatherosclerosis

Atherosclerosiscontributes to only 20%large artery IS; role inother IS uncertain

Age of Patient Broader Variation Most in > 65 y; higherrisk of ICH afterreperfusion

SafetyOutcomes

Lower risk of bleeding Increased risk ofbleeding

Composite vs Single Endpoints in IS Trials

• Can’t assume benefits of therapy from MI-prevention trials to IS-prevention 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 all-cause 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

Am J Med 2006;119:198-202

IndicationLowest Effective Dose

(mg/day)Primary Prevention Stroke in men 50+ Stroke in women 50+ Stroke with afibSecondary Prevention Stroke with hx TIA/IS Stroke/death with hx IS

Unknown> 100?

325

50160

Aggrenox: ESPS-237%*

16.3%*** 18.1%***

23.1%**

0

5

10

15

20

25

30

35

40

Rel

ativ

e R

isk

Red

uct

ion

%

ER DP/ASAvs PL

ER DP vs PL ASA vs PL ER DP/ASAvs 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 AggrenoxLancet 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 No

ASA Clopidogrel ASA + ER-DPASA Clopidogrel

Recurrent TIA/IS

Clopidogrel Or ASA

& Clopidogrel

Recurrent TIA/IS

No change, or Assess Risk

vs Benefit of combination Tx

Recurrent TIA/IS

No change* or ASA or Clopidogrel or ASA & ER-DP

Recurrent TIA/IS

ASA & ER-DP or Clopidogrel*

Recurrent TIA/IS

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

The left atrial appendage of a woman with atrial fibrillation who suffereda thromboembolic event. Organized 5mm thrombi are apparent. A 5mm thrombuscan completely occlude the middle cerebral artery.

Cardioembolic Stroke

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 2.72o Prx 8.4

64 (05% CI49-74)

Hart RG. Ann Intern Med 2007;146:857-67

Antiplatelet vs Placebo in AfibN 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 2836

300 mg/day1200 mg/day

0.90.7

1714

5 Trials 2834 50-1200 mg/day 1o Prx 1.92 o Prx 2.5

22(95% CI 2 to 39)

Hart RG. Ann Intern Med 2007;146:857-67

Warfarin vs ASA in AFN INR Target ARR (%/yr) RRR (%)

AFASAK I (89, 90)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 67AFASAK 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

8 Trials3647

1o Prx 0.72 o Prx 7

38 (18 to 52)

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

Warfarin vs Ctl/PL ASA vs CTL Warfarin vs ASA

N 2900 3762 3647

ICHEvents, nRRR (95% CI)ARR, %/yr

6 vs. 3NCNC

8 vs. 4NCNC

20 vs. 7-128 (-300 to –4)

-0.2Major extracranialhemorrhage, nRRR (95% CI)ARR, %/yr

31 vs. 17-66 (-235 to 18)

-0.3

16 vs. 152 (-98 to 52)

-0.2

40 vs. 22-70 (-234 to 14)

-0.2All-cause MortalityDeaths, nRRR (95% CI)ARR, %/yr

110 vs. 14326 (3 to 43)

1.6

184 vs. 204

14 (-7 to 31)0.5

117 vs. 1289 (-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 riskfeatures

SPAF Women > 75 y,SBP > 160 mmHg,LV dysfunction

No hx HT; No high riskfeatures

CHADS2 Score 3-6 Score 1-2 Score 0

Framingham 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

ACCP Prior IS/TIA/ embolism; > 75y;mod-severe LV function w/woHF; HT, DM

Age 65-75y, with noother RF

< 65 y with no RF

NICE/Birmingham

Prior IS/TIA/embolism; 75y w/HT, DM or vascular disease;valve disease or HF; impairedLV function

Age 65 with no highRF; age < 75 with HT,DM or vascular disease

Age < 65 with no hxembolism, HT, DM orother RF

ACC/AHA/ESC

Prior IS/TIA/embolism; valvedisease; more than 1 of: 75,HT, HF, impaired LV function;or DM

Age 75; HT; HF;impaired LV function;DM

AF (no other RF)

Antithrombotic Therapy for Patients with AFib

Risk Category Recommended Therapy

No Risk Factors1 Moderate RFAny High RF or >1Moderate RF

ASA 81-325 mg/dayASA 81-325 mg/day or Warfarin (INR 2-3)Warfarin (INR 2-3)

Weaker RF Moderate RF High HF

FemaleAge 65-74 y

CADthyrotoxicosis

75 yHTHF

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;6:981-93Paciaroni 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 contraindication to anticoagulation

Cryptogenic stroke

1. ASA or ASA/ER-DP

2. Clopidogrel

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

N Engl J Med 2006;355:549-59.

1.66 (1.08-2.55)Hemorrhagic

0.78 (0.66-0.94)Ischemic

0.87 (0.73-1.03)Nonfatal

0.57 (0.35-0.95)Fatal

0.84 (0.71-0.99)Any

Hazard ratio (95% CI) with atorvastatin

Type of stroke

O’Regan C. Am J Med 2008;121;24-33

Meta-Analysis of Stain Therapy for Stroke Prevention

All- stroke prevention:16% RRR (RR 0.84, CI 0.79-0.91)

Thiazide Diuretics

Angiotensin Conventing Enzyme Inhibitors (ACEIs)

Angiotensin Receptor Blockers (ARBs)

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 34Heart failure 42CHD 28CVD mortality 24Total mortality 10

ALLHAT

Psaty et al., JAMA 1997;277:739-45JAMA 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

Lancet. 2001 Sep 29;358(9287):1033-41Stroke 2005;36:2164-9

PROGRESS

ARBS for Secondary Stroke Prevention

LIFE

Lancet. 2002;359(9311):1004-10

LIFE. Lancet 2002;359:1004-10

ACCESS

Stroke. 34(7):1699-703, 2003 Jul.

• 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

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

Diener et al. J Neurol Sci 1996; 143: 1-13.

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