medications for secondary prevention of ischemic stroke alison alleyne, pharmd david thompson health...

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