double troublealfacalcidol 0.25mcg po 3x/week pantoprazole 40mg po daily . relevant review of...
TRANSCRIPT
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
14
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?