review of the updated guidelines on the inclusion/exclusion

Indications for Intravenous Alteplase in

Acute Ischemic Stroke: Guideline Update

Ganesh Asaithambi, MD

June 6, 2016

Disclosures

• None

2

Objectives

• Discuss differences between institutional guidelines on the implementation of intravenous (IV) alteplase for acute ischemic stroke (AIS)

• Differentiate alteplase package insert instructions vs evidence-based guidelines

• Discover potential missed opportunities in which alteplase can be used

3

Statement for Healthcare Professionals

4

Purpose

• Update guidelines from 2013

– Based largely from original NINDS Trial in 1996

• Response to updated alteplase FDA package insert February 2015

5

Variability in “Breaking” Exclusion Criteria

De los Rios F et al. J Stroke Cerebrovasc Dis 2014;23:2130-2138.

6

Defining the Recommendations

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

7

Defining the Recommendations

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Confession

• Far too many recommendations to review in short time period

• Review controversial or clinically relevant topics

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Topics Addressed

• Blood pressure control

• Presence of cerebral aneurysm

• Presence of arterial dissection

• Suspicion of infective endocarditis

• Mild and rapidly improving stroke symptoms

• Bleeding diathesis

• Individual criteria in the expanded time window (3-4.5 hours)

• Type of antithrombotic used prior to stroke

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Exclusion due to Blood Pressure

2013 Guidelines Revised FDA Package Insert

2016 Guidelines

Contraindication for sustained SBP > 185 mmHg or DBP

> 110 mmHg

Contraindicationwith severe

uncontrolled hypertension

Contraindicationfor sustained SBP > 185 mmHg or DBP

> 110 mmHg(Class I; Level of

Evidence B)

Jauch EC et al. Stroke 2013;44:870-947.http://www.gene.com/download/pdf/activase_prescribing.pdfDemaerschalk BM et al. Stroke 2016;47(2):581-641.

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Exclusion due to Cerebral Aneurysm

2013 Guidelines Revised FDA Package Insert

Contraindication Contraindication

Jauch EC et al. Stroke 2013;44:870-947.http://www.gene.com/download/pdf/activase_prescribing.pdf

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Presence of Cerebral Aneurysm

• Unruptured intracranial aneurysms (UIA) affect ~3% general population

– Increased use of noninvasive imaging will detect more

– Increase in incidence due to increase in elderly population

• Perceived fear of thrombolysis is limited to evidence by case reports

• Prospective and large case series

– Similar rates of symptomatic intracerebral hemorrhage (sICH)

– Small and moderate sized

– No evidence for large or giant sized

Vlak MHM et al. Lancet Neurol 2011;10:626-636.Asaithambi G et al. J Vasc Interv Neurol 2014;7:14-17.Demaerschalk BM et al. Stroke 2016;47(2):581-641.Goyal N et al. Neurology 2015;85:1452-1458.

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Presence of Cerebral Aneurysm

2016 Recommendations

Patients with AIS with known small or moderate-sized unruptured and unsecured cerebral aneurysms (< 10 mm), administration of IV alteplase is reasonable (Class IIa; Level of Evidence C)

Risk and usefulness of IV alteplase among AIS patients with large or giant aneurysms is not known (Class IIb; Level of Evidence C)

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Exclusion due to Arterial Dissection

2013 Guidelines Revised FDA Package Insert

Consider evaluating for aortic arch dissection if

clinically indicated

No warnings provided

Jauch EC et al. Stroke 2013;44:870-947.http://www.gene.com/download/pdf/activase_prescribing.pdf

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Presence of an Arterial Dissection

• Aortic arch dissection

– Evidence limited to case reports

– Fear of extension or rupture of dissection

• Cervical artery dissection (CAD)

– Pooled analyses vs registry-based controls has similar outcomes

– CADISS: 2015• Not independently associated with poor outcome or increased risk of sICH

– Clinical trials considered CAD patients eligible for treatment

Demaerschalk BM et al. Stroke 2016;47(2):581-641.Zinkstok SM et al. Stroke 2011;42;2515-2520.CADISS Investigators. Lancet Neurol 2015;14:361-367.

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Presence of an Arterial Dissection

• Intracranial dissections

– Restricted to case reports; few with thrombolysis

– When associated with aneurysm, higher risk of SAH/ICH• Posterior > anterior circulation associated with dissecting aneurysms and SAH

– Treatment for ischemic syndromes• Anticoagulation vs antiplatelet?

Demaerschalk BM et al. Stroke 2016;47(2):581-641.Asaithambi G et al. Int J Emerg Med 2015;7:44.

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Presence of an Arterial Dissection

2016 Recommendations

IV alteplase in AIS patients associated with aortic arch dissection is not recommended(Class III; Level of Evidence C)

IV alteplase in AIS patients associated with CAD is reasonably safe within 4.5 hours of onset and probably recommended (Class IIa; Level of Evidence C)

IV alteplase usefulness and safety in AIS patients associated with intracranial arterial dissections is unknown (Class IIb; Level of Evidence C)

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Exclusion due to Infective Endocarditis (IE)

2013 Guidelines Revised FDA Package Insert

Not an exclusion No warnings provided

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Presence of IE

• Not an exclusion in original NINDS study

• Embolic stroke is common complication of IE

– Infarcts are prone to hemorrhagic transformation due to septic arteritis with erosion of arterial wall

– Formation of mycotic aneurysms

• Guidelines only report results of cases

• Administrative database study

– Significantly higher rates of unfavorable outcomes

Demaerschalk BM et al. Stroke 2016;47(2):581-641.Asaithambi G et al. Stroke 2013;44:2917-2919.

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Presence of IE

2016 RecommendationsPatients with AIS and symptoms consistent with IE, IV alteplase is not recommended (Class III; Level of Evidence C)

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Exclusion due to Mild or Rapidly Improving Stroke Symptoms (RISS)

2013 Guidelines Revised FDA Package Insert

May be considered and potential increased risk

should be weighed against the anticipated benefits

No warnings provided

Jauch EC et al. Stroke 2013;44:870-947.

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Mild and RISS

• ~30-50% of all stroke patients

– Majority of these patients do not receive therapy

– Up to 1/3 have poor outcomes if not treated with alteplase

Romano JG et al. Stroke 2016;47;1278-1285.

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TREAT: The Re-Examining Acute Eligibility for Thrombolysis Task Force

• Organized to review criteria for treatment with alteplase• All panel participants including those previously involved in the NINDS

study agreed that a definition of RISS should be reserved for those who improve to a NONDISABLING mild deficit

• Patients with these features should be treated and would have been within the original NINDS study!!– Complete hemianopsia as only sign– Severe aphasia as only sign (≥2 on item 9)– Visual or sensory extinction (≥1 on item 11)– Any weakness limiting sustained effort against gravity (≥2 on items 5 or 6)– Any deficits that lead to a total of NIHSS>5 or – Any remaining deficit considered potentially disabling in the view of the

patient and the treating practitioner regardless of NIHSS value…clinical judgment required

Levine SR et al. Stroke 2013;44:2500-2505.

Nondisabling “MILD” Stroke

• PRISMS study

• IST3: post hoc analysis of clinical outcomes in PRISMS qualifying patients

Khatri P et al. Stroke. 2015;46:2325-2327

Mild or RISS

2016 Recommendations

For patients with mild but disabling symptoms, IV alteplase should not be withheld (Class I; Level of Evidence A)

Patients with mild, nondisabling symptoms alteplase can be considered; risks must be weighed against anticipated benefits (Class IIb; Level of Evidence C)

IV alteplase is reasonable for patients who present with moderate to severe strokes and demonstrate early improvement but remain impaired and potentially disabled (Class IIa; Level of Evidence A)

Delaying treatment to monitor for further improvement is not recommended (Class III; Level of Evidence C)

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Exclusion due to Bleeding Diathesis

2013 Guidelines Revised FDA Package Insert

Contraindication for knownbleeding diathesis

Contraindication for knownbleeding diathesis

Jauch EC et al. Stroke 2013;44:870-947.http://www.gene.com/download/pdf/activase_prescribing.pdf

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Bleeding Diathesis

• Any use of anticoagulants (warfarin, direct thrombin inhibitors, Factor Xa inhibitors)

• INR > 1.7 or PT > 15 seconds

• Platelet count < 100,000

• Use of heparin within 48 hours AND elevated aPTT

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Thrombocytopenia

• Derived by expert consensus (no evidence)

• Far too few reports on treatment for < 100,000

• Only 0.3% found to have thrombocytopenia when not suspected based on initial history

Demaerschalk BM et al. Stroke 2016;47(2):581-641.Cucchiara BL et al. Stroke 2007;38:1639-1640.

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Elevated INR (> 1.7)

• Medication effect

– Not attributable to other causes of coagulopathy

• Safety data derived from registries and observational studies

• Only 0.4% found to have elevated INR when not suspected based on initial history

Demaerschalk BM et al. Stroke 2016;47(2):581-641.Saposnik G et al. Stroke 2013;44:2755-2759.

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2016 Recommendations

2016 Recommendations

Safety and efficacy of IV alteplase for AIS patients with platelets < 100,000, INR > 1.7, aPTT > 40 seconds, or PT > 15 seconds are unknown. Its use is not recommended (Class III; Level of Evidence C)

If there is no reason to suspect an abnormal value, initiation of IV alteplase should not be delayed for results of platelet count or coagulation studies (Class IIa; Level of Evidence B)

Safety and efficacy of IV alteplase for AIS patients with clinical history of bleeding diathesis and should be considered on a case-by-case basis (Class IIb; Level of Evidence C)

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Exclusion Within the Expanded Time Window (3-4.5 hours)

2013 Guidelines Revised FDA Package Insert

Treat for eligible patients meeting ECASS III Trial

inclusion criteria

No treatment > 3 hours

Jauch EC et al. Stroke 2013;44:870-947.http://www.gene.com/download/pdf/activase_prescribing.pdf

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Additional Exclusion Criteria

• Age >80 years

• Any oral anticoagulant use regardless of INR value

• NIHSS >25

• History of prior stroke AND diabetes mellitus

• CT hypodensity >1/3 of MCA territory

Hacke W et al. N Engl J Med 2008;359:1317-1329.

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Increase in Treatment Utilization

Asaithambi G et al. J Stroke Cerebrovasc Dis 2014;23(9):2316-2321.

GWTG Registry 2009-2012

Cronin CA et al. Stroke 2014;45:2745-2749.

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GWTG Registry 2009-2012

Cronin CA et al. Stroke 2014;45:2745-2749.

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Treatment within 3-4.5 Hour Window

2016 Recommendations

IV alteplase is recommended in carefully selected patients meeting ECASS III criteria (Class I; Level of Evidence B)

For patients >80 years old, IV alteplase is safe and can be as effective as in younger patients (Class IIa; Level of Evidence B)

For patients taking warfarin and INR <1.7, IV alteplase appears safe and may be beneficial (Class IIb; Level of Evidence B)

AIS patients with history of stroke and diabetes mellitus, IV alteplase is a reasonable option (Class IIb; Level of Evidence B)

The benefit of IV alteplase among AIS patients with NIHSS >25 is uncertain (Class IIb; Level of Evidence C)

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Exclusion due to Antithrombotic Usage Prior to Stroke

2013 Guidelines Revised FDA Package Insert

Contraindication if on warfarin and INR >1.7

Warning if on warfarinContraindication if INR >1.7

Contraindication if on direct oral agents

Contraindication if on therapeutic doses of low molecular weight heparin

(LMWH)

Jauch EC et al. Stroke 2013;44:870-947.http://www.gene.com/download/pdf/activase_prescribing.pdf

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Antiplatelet Therapy

• 30-50% of patients treated with alteplase are on some antiplatelet

– Aspirin in majority

– Clopidogrel, dipyridamole, others???

– Newer thienopyridines (prasugrel, ticagrelor)???

• “Small” increased risk of sICH

– Did not affect probability of excellent outcome

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Warfarin

Xian Y et al. JAMA 2012;307:2600-2608.

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LMWH

• Contraindicated with use of therapeutic doses

• But DVT prophylactic doses??

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Novel Oral Anticoagulants

• Dabigatran

– Restricted to case reports• Only 1 case associated with sICH and death

– Thrombin time, ecarin clotting time is most sensitive• aPTT, PT not as reliable

• Rivaroxaban

– Even fewer case reports• Without adverse events

– Factor Xa activity assay• aPTT, PT not as reliable

• No reports with use of apixaban or edoxaban

42

Antithrombotic Use Prior to Stroke

2016 Recommendations

IV alteplase is recommended for patients taking antiplatelet monotherapy (Class I; Level of Evidence A)

IV alteplase is recommended for patients taking dual antiplatelet therapy (Class I; Level of Evidence B)

IV alteplase is reasonable in patients taking warfarin with INR ≤1.7 (Class IIb; Level of Evidence B)

IV alteplase is not recommended in patientswho received a dose of LMWH within the previous 24 hours – therapeutic or prophylactic (Class III; Level of Evidence B)

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Antithrombotic Use Prior to Stroke

2016 Recommendations

IV alteplase is not recommended forpatients taking direct thrombin or factor Xainhibitors as it may be harmful (Class III; Level of Evidence C)

Use of IV alteplase could be considered if coagulation studies such as aPTT, PT, INR, platelet count, ecarin clotting time, thrombin time, or direct factor Xa levels are normal or the patient has not received a dose <48 hours.

Demaerschalk BM et al. Stroke 2016;47(2):581-641.

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Institutional Recommendations

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American Academy of Emergency Medicine (2010)

• Alteplase is one treatment option for stroke when given in academic medical centers and prepared stroke centers

• Emergency physicians should have necessary resources to optimally care for suspected stroke patients

• Hospitals should formulate a plan for timely care of patients with suspected acute stroke

www.aaem.org/UserFiles/file/tissue_plasminogen_activator.pdf

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American College of Emergency Physicians (2015)

• IV alteplase should be offered and may be given to selected patients with AIS < 3 hours and within 3-4.5 hours after symptom onset at institutions where systems are in place to safely administer the medication. The increased risk for sICH should be considered when deciding treatment initiation (Level B)

• When feasible, shared decision making between the patient and medical team should be completed (Level C)

www.acep.org/Clinical---Practice-Management/ACEP-Current-Clinical-Policies/

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Conclusions

• When to treat

– < 4.5 hours from symptom onset

– SBP < 185 and DBP < 110

– Unruptured, unsecured cerebral aneurysm < 10 mm*

– Extracranial carotid or vertebral artery dissections*

– Mild and rapidly improving stroke symptoms (disabling)*

– INR < 1.7*

– Mono or dual antiplatelet therapy*

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Conclusions

• Consider treatment/up for debate

– Intracranial dissections

– Prasugrel/ticagrelor

– Direct oral anticoagulants with normal coagulation studies*

– Mild, nondisabling stroke symptoms*

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Final Thoughts

• Rigorous scientific data to support treatment among carefully selected patients

• Regardless of your take on the effectiveness of alteplase, informed consent should always be undertaken when feasible

– As long as it does not significantly delay treatment

• Embrace collaboration of all members of the care team in decision making and care for the patient

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Questions?

ganesh.asaithambi@allina.com

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