Double Trouble Role of dual antiplatelet therapy for ischemic strokes

Winnie Chan

LMPS Pharmacy Resident

Oct 11, 2016

Learning Objectives

• Describe the pathophysiology, clinical features, and therapeutic alternatives for secondary prevention of ischemic stroke.

• Describe the efficacy of dual antiplatelet therapy (DAPT) in the setting of ischemic strokes

• Describe the risk of bleeding with DAPT in the setting of ischemic strokes

• Apply the evidence for DAPT to our case patient

Meet the Patient ID 71 yo Caucasian male admitted 9/26, wt=66.5kg

CC 3 episodes of “slurred speech”

HPI 9/23: 1st episode of dysarthria in the evening, while watching TV (~20 secs) 9/24: 2nd episode of dysarthria (~1 min) 9/25: 3rd episode of dysarthria post-HD, lasting ~30 secs, difficulty writing lasting ~15 secs, left sided weakness 9/25: presented to Richmond hospital ER --> CT scan revealed dangling thrombus in R carotid artery. Transferred to VGH 9/26: Admitted to T11D

Social Hx

Allergies NKDA

PMH & MPTA

• HTN (10+ years)

• CAD (DES inserted Dec 2015)

• ESRD (Dx Dec 2015)

• Squamous cell carcinoma (Dx May 2016, RLL resection)

• Pulmonary embolism (June 2016)

• HFrEF (Most recent Echo July 2016: EF 30-40%)

Bisoprolol 1.25mg PO daily Ramipril 2.5mg PO daily Nitro patch 0.4mg/hr daily Atorvastatin 10mg PO daily (Dec 2015) Clopidogrel 75mg PO daily (Dec 2015) Tinzaparin 12000U SC daily (June 2016)

Renavite 1 tablet PO daily Calcium carbonate 1250mg x 1 at breakfast, 1 at lunch, 2 at supper Alfacalcidol 0.25mcg PO 3x/week Pantoprazole 40mg PO daily

Relevant Review of Systems Vitals BP=117/91, HR=68, RR=18, O2 Sat=94% RA, Temp = 36.6 ̊C

CNS Alert, Ox3 Good finger to nose coordination No syncope or presyncope, no pronator drift CT head (9/25): No ischemic changes in cerebral hemispheres. CTA (9/25): Moderate bilateral stenoses at cavernous segments of internal carotid arteries d/t atherosclerotic plaques. Hard + soft plaque in R common carotid artery.

HEENT Dysarthria, no visual changes, no headaches, no facial droop

CVS Normal heart sounds, no chest pain

RESP Normal breath sounds, no SOB

Liver/Renal SCr=306, eGFR =17, LFT’s WNL

LYTES WNL

HEME HgB = 118, MCV=94

Endo Lipids WNL, Random glucose=5.9

MSK Left sided weakness

Current Medications • Bisoprolol 1.25mg PO daily

• Ramipril 2.5mg PO hs

• Nitro patch 0.4mg/hr daily

• Atorvastatin 10mg PO daily

• ASA 81mg PO daily

• Clopidogrel 75mg PO daily

• Pantoprazole 40mg PO daily

• Calcium carbonate 500mg x 1 at breakfast, 1 at lunch, 2 at supper

• Alfacalcidol 0.25mcg PO 3x/week

• Renavite 1 tablet PO daily

• Tinzaparin 12000U SC daily

• PRN APAP 650mg PO q4h

Drug Therapy Problems • Patient is at risk of experiencing a major bleeding event secondary

to receiving DAPT and tinzaparin and would benefit from a reassessment of his antithrombotic therapies for CAD, secondary prevention of ischemic stroke and VTE treatment.

• Patient is at risk of experiencing another CV event and may benefit from a reassessment of his statin dose.

• Patient is receiving nitro patch with unclear indication and would benefit from reassessment of therapy.

Goals of therapy

• Reduce ongoing neurologic injury (dysarthria, L sided weakness)

• Reduce morbidity (long-term disability)

• Reduce mortality

• Prevent stroke recurrence

• Minimize ADRs from medications such as major bleeding events

8

Types of Stroke

Types of Ischemic Stroke

• TOAST Classification of Stroke Subtypes: ▫ Large artery atherosclerosis ▫ Cardioembolism ▫ Small vessel occlusion ▫ Stroke of other, unusual, determined etiology ▫ Stroke of undetermined etiology

• Ischemic stroke defined as infarction of CNS tissue ▫ Reduction or complete blockage of blood flow ▫ CT scan findings: hyperdense artery, loss of grey-white

differentiation ▫ Thrombosis: localized occlusive process within a blood vessel ▫ Embolism: clot or other material formed elsewhere within the

vascular system and lodges elsewhere to form blockage ▫ Systemic hypoperfusion: circulatory problem

Types of Ischemic Stroke

• Minor ischemic stroke ▫ Low score on NIHSS, absence of persistent neurologic deficit

• Transient ischemic attack (TIA) ▫ Transient episode of neurologic dysfunction caused by focal

brain, spinal cord or retinal ischemia without acute infarction

▫ Originally defined as sudden onset of focal neuro S/S lasting < 24 hours

Ischemic Stroke

• Risk factors: ▫ ↗ age, male, FHx of strokes, African-American descent ▫ HTN, Cardiac dx (Afib), diabetes, dyslipidemia, cigarette smoking

• Clinical Presentation: ▫ Weakness on one side of body, inability to speak, loss of vision,

vertigo, headache ▫ Dysarthria, visual field defects, altered LOC

• Diagnosis: ▫ CT head scan to rule out hemorrhage ▫ MRI will reveal areas of ischemia with higher resolution ▫ Holter monitor to determine if Afib is present ▫ TTE can detect valve or wall motion abnormalities that can be

sources of emboli

Carotid artery stenosis

• Carotid artery is large artery; pulse felt on either sides of neck under jaw

▫ Forks into internal & external carotid arteries

▫ Plaques often form at this division may break off & cause occlusion in smaller vessels leading to a stroke

• Management for symptomatic carotid atherosclerotic disease: Medications alone, carotid endarterectomy (CEA) or carotid artery stenting (CAS)

2014 AHA/ASA Guidelines for Prevention of Stroke in Patients with Stroke & TIA

• Revascularization should be considered in patients with recent TIA/ischemic stroke with 70-99% carotid artery stenosis if perioperative morbidity/mortality risk is low

• 50-69% carotid stenosis, consider CEA in context of patient-specific factors (age, sex, comorbidities) if perioperative morbidity/mortality is low

• <50% stenosis, no indication for CEA or CAS

• Patients at high risk of complication with CEA or CAS, effectiveness of revascularization vs. medical therapy alone is not well established

• Recommendations for medical management mirrors those for secondary prevention of ischemic stroke

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Carotid artery stenosis

Secondary prevention of ischemic

stroke • Lifestyle modification

• Antihypertensive therapy

• Glycemic control

• Statin therapy

• Antithrombotic therapy

▫ Antiplatelet therapy reduces incidence of stroke in those with high risk for atherosclerosis and those with known symptomatic cerebrovascular disease

▫ No statistically significant difference in terms of efficacy between aspirin & anticoagulant therapy (exception: Afib or risk factors for cardiogenic embolism)

ACCP 2012 Guidelines

Therapeutic alternatives • ASA

▫ Gold standard

• Extended release dipyridamole 200mg/ASA 25mg(Aggrenox) ▫ Recommended over ASA alone ▫ ESPS-2 & ESPRIT : Slightly more effective for secondary stroke

prevention ▫ Significant ADR headaches, $$$

• Clopidogrel ▫ Recommended over ASA alone ▫ CAPRIE: Overall benefit for combined endpoint of recurrent

stroke+MI+peripheral artery disease ▫ PRoFESS: Clopidogrel similar efficacy & bleeding rates as

compared to Aggrenox

• Combination ASA + Clopidogrel ▫ Not considered first line

PICO Question

P Patients with minor ischemic stroke or TIA

I ASA & Clopidogrel (DAPT)

C ASA or Clopidogrel alone

O Efficacy: • Time to another ischemic stroke Safety: • Bleeding

Search Strategy

Databases PubMed, EMBASE

Search term Ischemic stroke, secondary prevention, aspirin, clopidogrel

Exclusions Non-English Language Non-human studies

Results Pubmed – N=254, EMBASE - N=159 2 RCT (ASA+Clopidogrel vs ASA) 2 Meta-analysis Handful of review articles

Zhang et al 2015 Design SR and Meta-analysis

Studies 8 RCTs comparing DAPT and monotherapy (aspirin or clopidogrel)

Outcome Primary: Stroke recurrence Secondary: Major vascular events, major bleeding

Results Short term combination of clopidogrel+ASA is more effective than monotherapy (No increased risk of hemorrhagic stroke and major bleeding) Long term combination of clopidogrel+ASA does not reduce risk of stroke recurrence, and is associated with increased major bleeding.

Zhang et al 2015

CAS

37.5% had >50%

All had >50%

?

1.6% had >70%

All had >50%

?

?

?

Zhang et al 2015

Strengths Limitations

• Included RCTs • Well-defined outcomes • Randomization and allocation

concealment in trials

• Few studies; most were not adequately powered

• Significantly statistical heterogeneity

• Publication bias only published data were included which might overestimate effect of dual therapy

Zhang et al 2015

Conclusion: • Reaffirmed results from CHANCE DAPT has benefit in the short

term

▫ CHANCE is only trial that is properly powered

• If DAPT is considered, should limit it to 21 days

• Uncertain if ___ will benefit from DAPT, even in the first 90 days

Zhang et al 2015

CHANCE 2013 Multicentre (114 centres across China), randomized double-blinded, placebo-controlled, 90 days (n=5170)

P Inclusion criteria: • ≥ 40 yo, • Acute minor ischemic stroke or TIA • Drug w/in 24 hrs after Sx onset Exclusion criteria: - hemorrhage - major non-ischemic brain disease - isolated sensory Sx - indication for anticoagulation - heparin, OAC w/in 10 days - GI bleed/major surgery w/in 3 months - planned revascularization - severe non-CV comorbidities

I Clopidogrel 300mg on day 1, then 75mg/day on days 2-90 LD of ASA on day 1, then 75mg/day on days 2-21

C LD of ASA on day 1, then 75mg/day on days 2-90

O Primary: New stroke event at 90 days Secondary: moderate-severe bleeding, death

Patient demographics

CHANCE 2013

Characteristics No. (%)

ASA (n=2586) Clopidogrel+ASA (n=2584)

Age 62 63

Female sex 898 (34.7) 852 (33.0)

HTN 1683(65.1) 1716 (66.4)

CHF 38 (1.5) 42 (1.6)

Pulmonary embolism

1 (<0.1) 0

Qualifying event TIA Minor Stroke

728 (28.2) 1858 (71.8)

717 (27.7) 1867 (72.3)

Results:

Outcome No. (%)

ASA (n=2586) Clopidogrel+ASA (n=2584)

P value

Recurrence of stroke Ischemic Hemorrhagic

303 (11.7%) 295 (11.4) 8 (0.3)

212(8.2%) 204 (7.9) 8 (0.3)

HR = 0.68 (CI: 0.57-0.81) P<0.001

TIA 47 (1.8) 39 (1.5) P=0.36

Any bleeding 41 (1.6) 60 (2.3) P=0.09

CHANCE 2013

-Clopidogrel + ASA had ARR of 3.5%, NNT = 29 over 90 days - Trend towards increased overall bleeding with DAPT

Strengths Limitations

• Randomization and allocation concealment (automated system assigned number corresponding to a medication kit)

• Not industry funded • Intention-to-treat analysis • Minimal loss to follow-up • Met sample size to achieve 90%

power to detect 22% relative risk reduction with dual therapy, p=0.05

• Loading dose of ASA was determined by clinicians (75-300mg/day)

• Doesn’t quite fit our patient study excluded patients on heparin and OACs

• Study based in China ~5x higher risk of stroke than North America

CHANCE 2013

Conclusion: • Although clopidogrel & ASA has been shown to have no benefits in

the long term for stroke prevention, there seems to be benefits in the short term

▫ Clopidogrel + ASA for 21 days superior to ASA alone for subsequent stroke in first 90 days

• Caution when applying data from this trial onto ___

▫ Already on tinzaparin & clopidogrel when his possible “minor ischemic stroke” occurred

▫ risk of bleeding vs. benefits of increased efficacy for short term stroke prevention

CHANCE 2013

Back to our patient

• __ has risk factors for bleeding

• Hemodialysis

• Tinzaparin for PE treatment

• Does have addition indication for DAPT

▫ DES requires ideally 12 months of DAPT

▫ Minimum of 3-6 months for those at high risk of bleeding

My recommendations

• Discontinue ASA 81mg

• Continue tinzaparin 12000U SC daily and clopidogrel 75mg PO daily

▫ R/A tinzaparin in 3 months (recommended VTE treatment in cancer patients is 3-6 months)

▫ Clopidogrel more efficacious than ASA and should be considered if no significant financial burden

• Increase atorvastatin to 40mg PO daily

• Discontinue nitro patch

• Continue all other medications

Monitoring plan

Monitoring Parameter Expected Change Who When

Efficacy

Recurrence of stroke (=dysarthria, sensory changes, syncope, facial droop)

Absence MD RPh Nurse Patient

Ongoing

MI (=Chest pain, N/V, syncope) Absence

Recurrence of VTE Absence

Safety

Minor bleeding (cuts, bruises, epistaxis) Major bleeding (GI bleed, intracranial hemorrhage)

Presence at anytime MD RPh Nurse Patient

Ongoing

Hgb Decrease <90g/L MD, RPh q1m, q3m

Platelets Decrease <150 x 109/L MD, RPh q1m

What actually happened?

• Neurology consult thinks it is unlikely TIA/stroke; EEG ruled out seizures as well

• Removed Aspirin; Kept CR on tinzaparin & clopidogrel

• Removed nitro patch, increased atorvastatin to 40mg, kept all other medications

• ___ was medically stable throughout his stay at VGH

• Discharged home on 9/30

• Follow-up at the stroke prevention clinic scheduled

• Outpatient MRI later in Oct to evaluate for any other abnormalities

References • Cucchiara B, Messé S. Antiplatelet therapy for secondary prevention

of stroke In: UptoDate, Post TW(Ed), UptoDate, Waltham, MA (Accessed on October 2, 2016)

• Koziol K, Merwe V, Yakiwchuk E, Kosar L. Dual antiplatelet therapy for secondary stroke prevention. CFP. 2016; 62(8):640-645

• Wang et al. Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack. NEJM. 2013; 369(1): 11-19

• Zhang Q et al. Aspirin plus Clopidogrel as Secondary Prevention after Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis. Cerebrovascular Diseases. 2015; 39:13-22

• Kernan W, Ovbiagele B, Black H, Bravata D, Chimowitz M, Ezekowitz M et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-2236.

• Lansberg M, O'Donnell M, Khatri P, Lang E, Nguyen-Huynh M, Schwartz N et al. Antithrombotic and Thrombolytic Therapy for Ischemic Stroke. Chest. 2012;141(2):e601S-e636S.

Questions?