more tools in the toolbox antiplatelet therapy

10/8/21

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2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California

More Tools in the Toolbox: Updates in Antiplatelet Therapy for

Secondary Prevention of StrokeViet-Huong V. Nguyen, PharmD, MPH, MSc

Assistant Professor

Chapman University School of Pharmacy

Laura Tsu, PharmD, BCPS, BCGP, BCCPAssociate Professor

Chapman University School of Pharmacy

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Meet the Speakers – Viet Nguyen

Viet Nguyen, PharmD, MPH, MS is an Assistant Professor at Chapman University School of Pharmacy. She has served as a clinical pharmacist specialist in Neurology at the VA Greater Los Angeles and Harbor UCLA Medical Center, where she provides care to patients with stroke and other cerebrovascular disease. Dr. Nguyen has published on stroke risk factor management, adherence to stroke quality measures, and has a particular interest in stroke education.

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Meet the Speakers – Laura Tsu

Laura Tsu, PharmD, BCPS, BCGP, BCCP is an Associate Professor at Chapman University School of Pharmacy. She provides patient care to patients with cardiovascular disorders in the hospital setting, where she also works with patients after an acute stroke. Dr. Tsu has published articles in state and national journals about care of patients with cardiovascular disorders.

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Disclosure

• The speakers have nothing to disclose.

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Learning Objectives

1. List risk factors for non-cardioembolic stroke in older patients.2. Compare and contrast antiplatelet options in older patients with

ischemic stroke.3. Discuss the optimal duration of dual antiplatelet therapy post-stroke.4. Create a patient care plan for antiplatelet therapy for secondary

stroke prevention, including medication selection, monitoring, and education.

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American Heart Association / American Stroke Association

• Expert consensus document• An updated definition of stroke for the 21st century

• Ischemic stroke definition: • An episode of neurological dysfunction caused by focal central nervous

system (CNS) infarction (brain, spinal cord, retinal cell death)

Sacco et al. Stroke. 2013;44:2064-2089.

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Ischemic stroke epidemiology

• 690,000 ischemic strokes in the US annually • 185,000 (25%) are recurrent ischemic strokes• Risk of recurrent strokes reduced

• 8.7% à 5% from 1960 to 2000• 6845 recurrent strokes prevented/year• Reduction driven by secondary stroke preventive measures targeting stroke

etiology (e.g. blood pressure control) and use of antiplatelets

Kleindorfer et al. Stroke. 2021;52:00-00.

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Ischemic stroke etiologic subtypes

• Cardioembolic stroke• Lacunar stroke (caused by small

vessel disease)• Stroke caused by large

artery disease • Stroke from other causes• Cryptogenic stroke

• Imaging confirmed, embolic stroke of unknown source (ESUS)

• Imaging confirmed, non-embolic stroke of unknown source (non-ESUS)

Cardioembolic28%

Large artery 14%

Lacunar24%

Other2%

Cryptogenic (non-ESUS)

16%

Cryptogenic (ESUS)

16%

.Kleindorfer et al. Stroke. 2021;52:00-00.

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Ischemic stroke etiologic subtypes

• Cardioembolic stroke• Lacunar stroke (caused by small

vessel disease)• Stroke caused by large

artery disease • Stroke from other causes• Cryptogenic stroke

• Imaging confirmed, embolic stroke of unknown source (ESUS)

• Imaging confirmed, non-embolic stroke of unknown source (non-ESUS)

Cardioembolic28%

Large artery 14%

Lacunar24%

Other2%

Cryptogenic (non-ESUS)

16%

Cryptogenic (ESUS)

16%

.Kleindorfer et al. Stroke. 2021;52:00-00.

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Stroke etiology, risk factors, & treatmentStroke subtype Etiology Risk factors Treatment

Cardioembolic stroke

Atrial fibrillation, acute MI, heart failure, etc.

High CHADS-VASc score, etc.

Anticoagulation

Large artery stroke

Atherosclerosis 1. Blood pressure2. Diet3. Physical inactivity4. Smoking5. Abdominal obesity

Treating >1 risk factor = “additive” benefit

anti-hypertensive+

statin +

diet +

exercise+

anti-platelet

Lacunar stroke Long-standing hypertension and/or uncontrolled diabetes

Cryptogenic –ESUS

Unknown

Cryptogenic –non-ESUS

Unknown

Other Vasculitis, dissection, etc. Varies Varies

Kleindorfer et al. Stroke. 2021;52:00-00.ESUS = embolic stroke of unknown sourceMI = myocardial infarction

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Stroke etiology, risk factors, & treatmentStroke subtype Etiology Risk factors Treatment

Cardioembolic stroke

Atrial fibrillation, acute MI, heart failure, etc.

High CHADS-VASc score, etc.

Anticoagulation

Large artery stroke

Atherosclerosis 1. Blood pressure2. Diet3. Physical inactivity4. Smoking5. Abdominal obesity

Treating >1 risk factor = “additive” benefit

anti-hypertensive+

statin +

diet +

exercise+

anti-platelet

Lacunar stroke Long-standing hypertension and/or uncontrolled diabetes

Cryptogenic –ESUS

Unknown

Cryptogenic –non-ESUS

Unknown

Other Vasculitis, dissection, etc. Varies Varies

Kleindorfer et al. Stroke. 2021;52:00-00.ESUS = embolic stroke of unknown sourceMI = myocardial infarction

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Stroke type by NIH stroke scale severity (NIHSS)

• Mild strokes• Mild facial droop: NIHSS

1 or 2• Unilateral weakness that

is not complete: NIHSS 2,3,4

Category Scale

1a. Level of consciousness1b. LOC questions 1c. LOC commands

0-30-20-2

2. Best gaze 0-2

3. Visual fields 0-3

4. Facial Palsy 0-3

5a. Left motor arm5b. Right motor arm

0-40-4

6a. Left motor leg6b. Right motor let

0-40-4

7. Limb ataxia 0-2

8. Sensory 0-2

9. Best language 0-3

10. Dysarthria 0-2

11. Extinction and inattention 0-2

NIHSS Stroke severity0 No stroke symptoms1-4 Minor stroke5-15 Moderate stroke

16-20 Moderate-to-severe stroke21-42 Severe stroke

Scale definition0 = normal1 = drifts down2 = some effort 3 = limb falls4 = no movement

Scale definition0 = normal1 = minor paralysis2 = partial paralysis3 = complete paralysis

LOC = loss of consciousness

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Transient ischemic attack

• Historical definition (1960s):• sudden, focal neurological deficit of presumed vascular origin lasting 24

hours

• Revised definition (2009):• a transient episode of neurological dysfunction caused by focal CNS ischemia,

without acute infarction

*CNS = brain, spinal cord, retinaEaston et al. Stroke. 2009;40:2276-2293.

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TIA epidemiology and etiology

• 240,000 TIAs in the US annually• 15% of ischemic strokes preceded by TIAs• Mechanism and etiology of TIA can be difficult to identify since, by

definition, clinical symptoms are transient and brain imaging is negative• ABCD2 score is used to:

• predicts risk of stroke after TIA• assists with triaging real TIA versus TIA mimics

Kleindorfer et al. Stroke. 2021;52:00-00.Johnston et al. Lancet. 2007;369(9558):283-92.

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ABCD2 scoreABCD2

Score2-day

risk (%)7-day risk

(%)90-day risk (%)

Low(0-3)

1 1.2 3.1

Moderate (4-5)

4.1 5.9 9.8

High(6-7)

8.1 11.7 17.8

Risk factor Score

Age > 60 years 1

Blood pressure elevated at time of stroke

1

Unilateral weakness 2

Speech disturbance w/out weakness

1

Duration of symptom > 60 minutes

2

Duration of symptoms 10-50 minutes

1

Diabetes 1

Johnston et al. Lancet. 2007;369(9558):283-92.

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Question 1

HN is a 59-year-old male who presents to the ED with symptoms of right-sided numbness concerning for TIA. His BP on exam is 120/80 and he has a PMH of diabetes mellitus. Which of the following factors indicate he is at increased risk of a stroke within the next 90-days?A. his age

B. unilateral numbness on examC. blood pressure on presentationD. PMH of diabetes mellitus

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Ischemic stroke and TIA

• AHA/ASA guidelines state that ischemic stroke and TIA should be treated the same in terms of secondary prevention• New to 2021 AHA/ASA guidelines is reference to stroke etiologic

subtypes, NIHSS stroke severity, and TIA based on ABCD2 score


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Antiplatelet regimens recommended for secondary prevention of ischemic stroke or TIA• Monotherapy

• Aspirin• Clopidogrel• Aspirin + extended-release dipyridamole combination formulation

• Dual antiplatelet therapy (DAPT)• Aspirin & clopidogrel• Aspirin & ticagrelor


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Site of antiplatelet action

Degroot et al. Handbook Exp Pharmacol. 2012;210:87-110.

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Aspirin Aspirin + dipyridamole ER

Clopidogrel Ticagrelor

Mechanism of action

Irreversibly inhibits COX-

enzymes inhibiting production of

thromboxane A2

Inhibits adenosine deaminase and

phosphodiesterase

P2Y12 inhibitor P2Y12 inhibitor

StrokeDosing

50-325 mg daily 1 capsule BID(200mg dipyridamole ER and 25mg aspirin)

75 mg daily 90 mg BID

Adverse effects

Bleeding Bleeding, headache, dizziness, nausea,

dyspepsia

Bleeding Bleeding, dyspnea

CYP drug interactions

Not clinically significant

Not clinicallysignificant

CYP2C19 inhibitors

CYP3A4 inhibitor and inducers

Antiplatelet pharmacology

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Evidence for secondary prevention• Monotherapy with aspirin,

clopidogrel or aspirin/dipyridamole• CAST• IST• CAPRIE• ESPS-2• Esprit• PROFESS

• Ticagrelor• Monotherapy

• SOCRATES• Dual antiplatelet therapy

• THALES

• Dual antiplatelet therapy with clopidogrel and aspirin• Long-term (> 90 days)

• MATCH• CHARISMA• SPS3

• Short-term (21-90 days)• CHANCE• POINT• SAMMPRIS

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Antiplatelet monotherapy

Intervention Main finding

CAST (1997) Aspirin 160mg daily vs placebo within 48 hours of acute stroke

Aspirin decreased mortality and recurrent stroke with no significant difference in hemorrhagic stroke

IST (1997) Aspirin 300mg daily vs unfractionated heparin (5000 or 12,500 units) started immediately and up to 14 days

No difference in stroke or death with UFH. Aspirin had lower rate of death at 6 months. No difference hemorrhagic stroke.


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Intervention$ Population Mean duration of follow-up

Outcome: stroke recurrence/safety

CAPRIE (1996)

Clopidogrel 75mgvs.

ASA 325mg

Prior non-cardioembolic stroke, PAD, MI

1.91 years 5.3%# clopidogrel; 5.8%# ASAAbsolute RR 0.5% (NNT 200)Relative RR 0.91*Safety similar

ESPS-2 (1996)

ASA 50mg vs. Aspirin 25mg/

Dipyridamole (DPD) 200mg ER BID vs.

placebo vs dipyridamole

Prior non-cardioembolic stroke or TIA

2 years 9.9% DPD/ASA; 12.9% ASAAbsolute RR 3% (NNT 33)Relative RR 0.76*(15.8% Placebo)Safety similar

Esprit (2007)

ASA 30-325mg vs.

ASA + dipyridamole ER (400mg)

Prior non-cardioembolic stroke

3.5 years 13% DPD/ASA; 16% ASAAbsolute RR 3% (NNT 33)Relative RR 0.8*Safety similar

PROFESS (2009)

Clopidogrel 75mg vs.ASA 25mg/

dipyridamole 200mg ER BID

2.5 years 8.8% clopidogrel9.0% dipyridamole/ASARRR 1.02 (CI 0.92-1.11)Safety similar

Antiplatelet monotherapy

$ = daily dosing unless otherwise indicated* = statistically significant

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DAPT versus monotherapy in the long-termIntervention Population Mean duration of

follow-upOutcome: Stroke/MI recurrence and safety

MATCH (2004)

ASA 75mg + clopidogrel 75mg

vs. clopidogrel 75mg

Recent stroke or TIA 1.5 years (stopped early due to

increased risk of bleeding)

-No significant difference in stroke, MI, or vascular death-↑ bleeding events with DAPT

CHARISMA (2006)

Aspirin 75-162mg +clopidogrel 75mg

vs. placebo + aspirin

CVD or multiple CV risk factors

2.3 years -No difference in reducing stroke, MI, or death-No differences in bleeding

SPS3 (2012) Clopidogrel 75mg +aspirin 325mg

vs.placebo + aspirin

Recent lacunar infarcts

3.4 years -No difference in recurrent stroke prevention-↑ Major hemorrhage & all-cause mortality with DAPT

Diener et al. Lancet. 2004;364:331-7; Bhatt et al NEJM. 2006:354:1706-1771.; SPS3. NEJM. 2012;367:817-25.

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DAPT vs monotherapy in the short-termIntervention Population Duration of

follow-upOutcome: stroke recurrence

Outcome: safety

CHANCE (2013)

Clopidogrel 300 mg àCPG 75 mg +

ASA 75 mg x 21 days àCPG 75 mg daily

vs. Placebo + ASA 75 mg

Early minor ischemic stroke (NIHSS >3)or high-risk TIA (ABCD2

>4)

90 days 8.2% DAPT11.7% aspirinAbsolute RR 3.5% (NNT 29)Relative RR 0.68*

Moderate-severe hemorrhage: 0.3% in both groups (p=0.73)

POINT(2018)

Clopidogrel 600 mg àCPG 75mg +

ASA 50-325mg x 90 days vs.

Placebo + aspirin 50-325mg daily

x 90 days

Early minor ischemic stroke (NIHSS >3)or high-risk TIA (ABCD2

>4)

90 days 5.0% DAPT6.5% aspirinAbsolute RR 1.5% (NNT 67)Relative RR 0.75**

Major hemorrhage: 0.9% DAPT 0.4% aspirin (HR 2.32, 95% CI 1.1-4.87, p=0.02)

Wang et al. NEJM. 2013;369(1):11-9.Johnston et al. NEJM;379(3):215-225.

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DAPT in the short-term for large artery strokesIntervention Population Duration of

follow-upOutcome: stroke recurrence or death

SAMMPRIS (2011)

Aggressive medical management

(ASA 325mg + clopidogrel 75mg) x 90 days

vs. Aggressive medical

management +

angioplasty and stenting

Recent TIA or stroke attributed to severe symptomatic large artery disease (e.g. 70 to 99% stenosis of a major intracranial artery)

1 year(Enrollment

stopped early due to 30-day

outcome)

30 days14.7% medical management + stent5.8% medical managementNNH 11

1 year12% medical management20% stent

Chimowitz et al. NEJM. 2011;365:993-1003.

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Ticagrelor in ischemic strokeIntervention Population Duration

follow-upOutcome: stroke recurrence

Outcome: safety

SOCRATES Ticagrelor (TCG) 180mg x day 1 àTCG 90mg BID

day 2-90 vs.

ASA 300mg x day 1 àASA 100mg

day 2-90

Non-severe stroke (NIHSS <5) or high-risk TIA (ABCD2 >4)

90 days Stroke: 5.9% ticagrelor 6.6% ASAAbsolute RR 0.7% Relative RR 0.87, (95% CI 0.76-1.00, p=0.07)

Major bleeding: 0.5% ticagrelor 0.6% ASA

ICH: 0.2% ticagrelor0.3% ASA

THALES TCG 180mg + ASA 300mg x day 1

à TCG 90mg BID + ASA 75-100 mg x 30 days

vs. Placebo + aspirin

Non-severe stroke (NIHSS <5) or high-risk TIA (ABCD2 >4)

30 days Stroke or death: 5.5% DAPT6.6% ASAAbsolute RR: 1.1%(NNT 91)Relative RR 0.83* (95% CI 0.71-0.96, p=0.02)

Severe bleeding: 0.5% DAPT 0.1% ASA (p=0.001)

Johnston et al. NEJM. 2016;375:35-43.Johnston et al. NEJM. 2020;383(3):207-225.

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Question 2Which study supports the short-term use of clopidogrel in combination with aspirin in patients with recent stroke or TIA?

A. CASTB. POINTC. THALESD. CHARISMA

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2021 Guidelines take home message concerning anti-platelets• Antithrombotic therapy, including antiplatelets or anticoagulation, is

recommended for nearly all patients without contraindications• With very few exceptions, the combination of antiplatelets and

anticoagulation is typically not indicated for secondary stroke prevention• In non-cardioembolic ischemic stroke or TIA, antiplatelet therapy is

preferred over anticoagulation to minimize the risk of bleeding• Aspirin 50-325mg daily• Clopidogrel 75mg daily• Aspirin 25mg with dipyridamole 200mg BID


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2021 Guidelines take home messages

• Dual antiplatelet therapy is not recommended long term (> 90 days)• Short term (21-90 days), dual antiplatelet therapy is recommended

only in very specific patients (see next slide)• Typical dual antiplatelet therapy regimens are:

• Aspirin 81mg + clopidogrel 75mg daily• Aspirin 81mg + ticagrelor 90mg po BID (may increase risk of serious bleeding)


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Patients eligible for DAPTType of stroke/TIA Aspirin + Clopidogrel

Duration of therapyAspirin + Ticagrelor *Duration of therapy

High-risk TIA (ABCD2 ≥ 4) 21-90 days 30 days

Early arriving minor stroke (NIHSS ≤ 3) 21-90 days 30 days

Early arriving moderate stroke (NIHSS <5)

not eligible 30 days

Recent stroke/TIA due to severe (70-99%) intracranial stenosis

90 days$ 30 days

Recent stroke/TIA due to >30% intracranial stenosis of ipsilateral artery

not eligible 30 days

*=may increase risk of serious bleeding$= ASA dose here can be 375mg Kleindorfer et al. Stroke. 2021;52:00-00.

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Patient Case – Question 3

LE is an 81-year-old who was recently discharged from the local community hospital to your nursing home for continued rehabilitation following his large artery stroke attributable to severe (>70%) stenosis. What is the most likely etiology of LE's large artery stroke?A. emboli from cardiac thrombus

B. emboli from atherosclerosisC. hypertensive diseaseD. diabetes mellitus

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LE’s medication list is missing upon transfer to your rehab facility. However, verbal communication from the acute care hospital indicates that LE should be on antithrombotic therapy for stroke prevention. What is the most appropriate antithrombotic regimen for LE at this time?A. aspirin 325mgB. aspirin 325mg + ticagrelor 90mg BIDC. aspirin 81mg + warfarinD. aspirin 325mg + clopidogrel 75mg

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The appropriate antithrombotic regimen is initiated for LE at the rehab center on day 7 post-stroke. LE does well during rehab and suffers no side effects from his antithrombotic therapy. He is discharged from your rehab center 21 days after his initial stroke. What should his discharge papers indicate regarding his antithrombotic therapy?A. continue current antithrombotic regimen indefinitely unless contraindications ariseB. continue current antithrombotic regimen for an additional 69 days post stroke and then return to clinic to transition to a new regimenC. continue current antithrombotic regimen for an additional 9 days post stroke and then return to clinic to transition to a new regimenD. initiate new antithrombotic regimen at discharge

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Questions?

Viet Nguyen – [email protected] Tsu – [email protected]

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References

• Bhatt et al NEJM. 2006:354:1706-1771.• Campbell et al. Nat Rev Dis Primers/

2019;10(5):70• Caprie Steering Committee. Lancet.

1996;348(9038):1329.• Chimowitz et al. NEJM. 2011;365:993-1003.• Degroot et al. Handbook Exp Pharmacol.

2012;210:87-110.• Diener et al. J Neurol Sci. 1996;143(1-2):1.• Diener et al. Lancet. 2004;364:331-7;• Easton et al. Stroke. 2009;40:2276-2293.

• Esprit Study Group. Lancet. 2006; 367(9523): 1665.

• Johnston et al. Lancet. 2007;369(9558):283-92.• Johnston et al. NEJM. 2018;379(3):215-225.• Johnston et al. NEJM. 2016;375:35-43.• Johnston et al. NEJM. 2020;383(3):207-225.• Kleindorfer et al. Stroke. 2021;52:00-00.• Sacco et al. NEJM. 2008;359(12):1238.• Sacco et al. Stroke. 2013;44:2064-2089.• SPS3 Study Group. NEJM. 2012;367:817-25• Wang et al. NEJM. 2013;369(1):11-9.

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