7/12/2017 FSHP 2017 ANNUAL MEETING. Contemporary Therapeutics of Stroke Management Cardiovascular Track

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1 FSHP Contemporary Therapeutics of Stroke Management Cardiovascular Track Daniel A. Jackson, Pharm.D., BCPS Mayo Clinic in Florida Disclosure Published case series on intraventricular nicardipine Lu N, et al. Neurocritical Care Study site co-investigator for the NEWTON study Hanggi D, et al. Neurocritical Care I do not have (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity. Objectives Describe the etiology and pathophysiology of ischemic and hemorrhagic stroke Discuss fibrinolytic therapy for ischemic stroke Evaluate role of pharmacologic agents in combination with radiographic stroke interventions Discuss therapeutic options for treatment of hemorrhagic stroke Introduction Nearly 800,000 people in the United States have a stroke every year 75% being first-time strokes Stroke is the No. 5 cause of death in the United States, killing nearly 130,000 people a year Someone has a stroke every 40 seconds Someone dies of stroke every 4 minutes Stroke is a leading cause of long-term disability Leading preventable cause of disability. More women than men have strokes each year Women live longer American Stroke Association. Strokeassociation.org Ischemic Stroke Etiology Accounts for 87% of all strokes Types of ischemic stroke Thrombotic atherosclerotic plaque buildup Embolic traveled to the brain Prognosis is improving with newer treatment options 32% mortality Modifiable risk factors Hypertension, heart disease, smoking and diabetes Non-modifiable risk factors Increase risk as we get older African-American ethnicity American Stroke Association. Strokeassociation.org 1

2 Pathophysiology Occurs when an artery to the brain is blocked Surrounding brain tissue becomes hypo-perfused Known as the penumbra Collateral blood flow is responsible for keeping this tissue alive Penumbra will progress to infarction without treatment Patients will present with corresponding neurological deficits Treatment Mainstay of ischemic stroke treatment for the past 20 years Should be administered as quickly as possible Best outcomes with therapy in the first 90 minutes Endovascular Therapy Newer therapies for ischemic stroke Can be combined with IV thrombolysis in select patients American Stroke Association. Strokeassociation.org Treatment Goals Three principles of acute stroke care 1 Achieve timely recanalization of the occluded artery and reperfusion of the ischemic tissue Optimize collateral flow Avoid secondary brain injury Treatment targets the penumbra Glycemic control SHINE Trial 2 Temperature control Preventing infections Recombinant Tissue Plasminogen Activator (rtpa) Marketed as generic alteplase Only fibrinolytic agent approved for ischemic stroke in the US Treatment within 3 hours of symptom onset Effective in improving functional outcomes up to 4.5 hours Alteplase Dose: 0.9 mg/kg 10% administered as a bolus IV PUSH over 1 minute Remaining 90% given over 1 hour Can administer via peripheral or central line Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial. ClinicalTrials.gov Initial Patient Evaluation Focuses on eligibility for reperfusion therapy Time the patient was last known to be well Contraindications to thrombolytic therapy Focused neurological examination National Institutes of Health Stroke Scale (NIHSS) Capillary glucose level Blood pressure Computed tomography (CT) scan Indications and Contraindications for rtpa Originated as the exclusion criteria in major stroke trials Expert consensus for the National Institute of Neurological Disorders and Stroke (NINDS) trial American Heart Association published guidelines for use in 2013 These have been revisited in 2015 American Heart Association Scientific Statement FDA updates alteplase package insert in 2015 Resulted in more patients being considered for treatment Safety and efficacy still not well established for patients less than 18 years old 2

3 American Heart Association Guideline 2013 FDA Package Insert Update 2015 Indication: Diagnosis of ischemic stroke with measurable neurological deficit Symptom onset within 4.5 hours Symptom onset within 3 hours Age 18 years Warning for age > 77 and hemorrhage risk Contraindications Ischemic Stroke within 3 months Arterial puncture at non-compressible site within 7 days Blood glucose < 50 mg/dl CT showing hypodensity > 1/3 of the cerebral hemisphere Previous intracranial hemorrhage Systolic Blood Pressure (SBP) > 185/110 mmhg Bleeding diathesis (INR for warfarin, aptt for heparin, and platelets) Warning, contraindicated only with active hemorrhage Values removed, contraindicated for severe uncontrolled hypertension Laboratory values removed, contraindicated for any bleeding diathesis American Heart Association Guideline 2013 FDA Package Insert Update 2015 Relative contraindications Minor stroke (NIHSS < 5) Rapidly improving symptoms Seizure at onset with postictal residual deficits Acute myocardial infarction within 3 months Pregnancy Warning (Category C) Major extracranial trauma within 14 days Warning Major surgery within 14 days Warning Gastrointestinal or genitourinary surgery within 21 days Warning Alteplase package insert. US Food and Drug Administration. American Heart Association. Heart.org Alteplase package insert. US Food and Drug Administration. American Heart Association. Heart.org American Heart Association Guideline 2013 Contraindications for the hour window Age > 80 years Warfarin use (regardless of INR) NIHSS > 25 Previous stroke or diabetes mellitus American Heart Association Scientific Statement 2015 Recommend rtpa Probably recommend rtpa if INR < 1.7 Risk and benefit unknown Probably recommend rtpa FDA Package Insert Update 2015 FDA has only approved rtpa for use within 3 hours of symptom onset Efficacy Data rtpa infused in the first 3 hours increases the chances of functional independence by 1/3 at 3 months Stronger benefit seen if given within 90 minutes Number needed to treat (NNT) 0-90 minutes: 3.6 NNT from minutes: 4.3 NNT from minutes: 5.9 Alteplase package insert. US Food and Drug Administration. American Heart Association. Heart.org Safety Data Hemorrhage is the most dangerous complication ( %) Most cases caused by reperfusion injury Number needed to harm (disability or death): 126 Increased risk seen in certain patients Old age, diabetes, hyperglycemia, and uncontrolled hypertension Hemorrhagic Conversion Stop infusion if there is sudden neurological decline Obtain a STAT CT Treat hypertension with systolic target mmhg Administer cryoprecipitate 10 units or an anti-fibrinolytic agent Tranexamic acid mg/kg IV over 20 minutes Aminocaproic acid 5g IV followed by 1g/hour infusion Additional cryoprecipitate if fibrinogen remains <150 mg/dl Orolingual angioedema Rare but potentially serious side effect 3

4 Endovascular Therapy Six recent publications have recently advanced endovascular therapy to evidence based treatment MR CLEAN 1 ESCAPE 2 EXTEND-IA 3 SWIFT PRIME 4 REVASCAT 5 THRACE 6 Endovascular Therapy Benefits seen in selected patients Large proximal intracranial artery occlusion Carotid artery Middle cerebral artery segments 1 and 2 Performed within 6 hours of symptom onset Candidates for endovascular therapy Age 18 with NIHSS 6 Time from symptom onset to groin puncture < 6 hours Alberta Stroke Program Early CT Score (ASPECTS) 6 on baseline CT scan Proximal intracranial artery occlusion on CT scan 1. Berkhemer OA et al. N Engl J Med Goyal M et al. N Engl J Med Campbell BC, et al. N Engl J Med Saver JL, et al. N Engl J Med Kane DH, Park J. J Korean Neurosurg Soc Politi M et al. Endovascular Therapy for Acute Stroke. 5. Javin TG, et al. N Engl J Med Prog Cardiovasc Dis Bracard S, et al. Lancet Neurology Endovascular Therapy CT angiogram or perfusion required for patient selection Transfer to a comprehensive stroke center Can be safely performed in patients who received full dose rtpa NNT: 3-7 To help one additional patient regain functional independence NNT: 2.6 To reduce disability by one level on the modified Rankin Scale Endovascular Therapy Efficacy Data Higher rates of reperfusion Better functional outcomes Efficacy seen in patients older than 80 years Good outcomes in patients with severe strokes NIHSS >20 Newer retrievable stents and aspiration techniques are more effective than their predecessors Safety Data Symptomatic intracerebral hemorrhage (sich) is the main adverse effect Occurred in 4.4% of all patients in the six main studies Kane DH, Park J. J Korean Neurosurg Soc Politi M et al. Endovascular Therapy for Acute Stroke. Prog Cardiovasc Dis Kane DH, Park J. J Korean Neurosurg Soc Politi M et al. Endovascular Therapy for Acute Stroke. Prog Cardiovasc Dis Special Considerations Wake-up strokes Challenging patients unknown time of symptom onset Formal contraindication to IV rtpa Select patients may benefit from reperfusion therapy No evidence of large infarction on presentation Ongoing studies ClinicalTrials.gov DAWN POSITIVE DEFUSE 3 MR WITNESS Stern GM et al. Thrombolytic Therapy in Wake-Up Stroke. Clinical Neuropharmacology Special Considerations Newer oral anticoagulants rtpa can be given in warfarin patients with INR 1.7 No safety data with newer oral anticoagulants Available lab studies can not accurately quantify the degree of anticoagulation IV thrombolysis should not be given Endovascular therapy for proximal large vessel occlusion Minor or rapidly improving deficits 33% of patients who don t receive rtpa are disabled at 3 months Ongoing Study ClinicalTrials.gov PRISMS 4

5 Special Considerations Posterior circulation strokes Basilar artery occlusions can be devastating IV rtpa and endovascular therapy from registry data show functional independence in 30-40% of cases Endovascular therapy is currently being studied Basilar Artery International Cooperation Study (BASICS) Mortality remains high even in the reperfusion groups 30-35% New treatment considerations for basilar artery occlusion No evidence of large pontine or cerebellar infarction Extend the IV rtpa window past 4.5 hours Extend the endovascular therapy window beyond 6 hours Hemorrhagic Stroke Etiology Hemorrhagic stroke accounts for 13% of all strokes Two main types of hemorrhagic stroke Intracranial hemorrhage Subarachnoid hemorrhage Poor prognosis Mortality (32-67%) and high incidence of poor outcomes Most common modifiable risk factor hypertension Seen in 50-70% of patients with a hemorrhage Other risk factors Coagulopathies, anticoagulant use, congenital or systemic disease like thrombocytopenia American Stroke Association. Strokeassociation.org Pathophysiology Results from a weakened blood vessel that ruptures and bleeds Types of weakened blood vessels Aneurysms Arteriovenous malformation Blood will accumulate and compress the surrounding tissue American Stroke Association. Strokeassociation.org Rapid diagnosis and focused management are crucial Signs of Sudden onset Focal neurological deficits Severe headache Vomiting Systolic blood pressure > 220 mmhg Pertinent Medical History Hypertension, prior stroke, head trauma, and anticoagulants Diagnosis confirmed by CT or MRI 5

6 Goal is prevention of secondary brain injury caused by Hematoma expansion Intraventricular hemorrhage (IVH) extension Raised intracranial pressure (ICP) Fever Principles of early medical management Airway management Cardiovascular support Lowering of blood pressure Reversal of anticoagulants ICP control Blood pressure management Elevated pressures are associated with hematoma expansion Goal blood pressure in the acute phase is not clearly defined Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage (INTERACT 1) trial 1 Intensive blood pressure lowering effects on hematoma expansion Significantly lower incidence of hematoma expansion at 24 hours in the intensive blood pressure lowering group No difference in 90 day functional outcomes 1. Anderson CS, et al. Lancet Neurology Blood pressure management Rapid Blood Pressure Lowering in Patients with Acute (INTERACT 2) trial 1 Phase III trial evaluating intensive blood pressure reduction Trend towards lower death and disability in the intensive arm Significant decrease in the odds of poor functional outcome 1. Anderson CS, et al. N Engl J Med Blood pressure management Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) trial 1 Safety of intensive blood pressure lowering with IV nicardipine No significant difference in hematoma expansion and functional outcome measures Intensive Blood Pressure Lowering in Patients with Acute (ATACH 2) trial 2 Evaluate intensive blood pressure reduction within 4.5 hours No significant difference in death and disability or the incidence of hematoma expansion 1. Qureshi AI, et al. Arch Neurol Qureshi AI, et al. N Engl J Med Blood pressure management Current evidence supports Early intensive blood pressure lowering is safe and feasible and is associated with a modestly better functional outcome Intravenous infusion may be warranted for Systolic Blood Pressure (SBP) >220 mmhg 2015 AHA/ASA guidelines for the management of spontaneous ICH Early blood pressure reduction Goal SBP of 140 mmhg if presenting with SBP mmhg Anticoagulation Reversal Anticoagulants are usually not the primary cause Increased risks with patients taking anticoagulants Higher chance of secondary hemorrhage expansion Increased death Increased survival with poor functional outcome Reversal agents have not been extensively studied in this unique population Data and recommendations often come from small studies including those not in hemorrhage patients Frontera JA, et al. Neurocritical Care

7 Anticoagulation Reversal Neurocritical Care Guidelines for using antithrombotic reversal agents in intracranial bleeding emergencies 2016 Discontinue the antithrombotic first then consider reversal Reversal is not always indicated for each patient Small radiographic hemorrhage Mildly abnormal coagulation parameters Anticoagulants with very short half-lives Anticoagulation Reversal Potential benefits of reversal include Improved outcomes and reduced mortality May prevent further hemorrhage expansion Correction of abnormal coagulation parameters Things you should consider prior to reversal Anticoagulant s mechanism of action Metabolism and elimination pharmacokinetics Effects of hepatic and renal impairment Hemodialysis (HD) or continuous renal replacement therapy (CRRT) drug removal? Frontera JA, et al. Neurocritical Care Frontera JA, et al. Neurocritical Care Anticoagulation Reversal Activated charcoal within 2 hours Give antidote if available Consider administration of additional agents after evaluating the risk versus benefit Fresh Frozen Plasma (FFP) 3 or 4 factor Prothrombin Concentrate Complex (PCC) Activated Prothrombin Concentrate Complex (apcc) Recombinant factor VIIa Frontera JA, et al. Neurocritical Care Anticoagulant Warfarin Heparin, Enoxaparin, Dalteparin Dabigatran Factor Xa inhibitors Factor Xa Inhibitors, Direct thrombin inhibitors Antidote Vitamin K Protamine Idarucizumab Andexanet alfa (Investigational) Aripazine (Investigational) Anti-platelet reversal Discontinue the antiplatelet agent Platelet transfusion data is lacking Potential role for desmopressin (DDAVP) Awaiting results from ongoing study - ClinicalTrials.gov Platelet Transfusion in Spontaneous Intraparenchymal Hemorrhage (PATCH) trial Thromboprophylaxis Weigh the risk of bleeding and thrombosis Prophylaxis should not be delayed Intermittent pneumatic compression, systemic anticoagulation, or an IVC filter Frontera JA, et al. Neurocritical Care Intracranial hypertension Role for ICP monitoring in select ICH patients ICP medical management Short term hyperventilation Mild sedation Hyperosmolar therapy Mannitol Hypertonic Saline Therapeutic hypothermia Mannitol 20% Sodium Chloride 23.4% Dose g/kg ml IVPB over IVPB over Infusion min min Osmolarity 1098 mosm/l 8008 mosm/l Access Clinical Monitoring Central line preferred Serum osmolarity Osmolar gap Electrolytes Fluid balance Central line Serum sodium levels Temperature control Fever incidence is high and is associated with poor outcome Management Antipyretic medications are first line Acetaminophen NSAIDS External cooling devices Infusion of cold saline Mild therapeutic hypothermia Considered investigational May reduce edema around the hemorrhage site 7

8 Glucose control Hyperglycemia is associated with increased death in ICH Hypoglycemia also associated with higher mortality Goal is standard glucose control Seizure Management Seizures occur in up to 33% of patients after ICH Incidence is highly dependent on the location of the bleed Monitoring is recommended for decreased mental status of unknown etiology Prophylaxis has not shown to be beneficial and is not recommended Surgical Management Hematoma evacuation Decompression craniotomy Placement of an External Ventricular Drain (EVD) ICP measurement and therapeutic drainage Used with intraventricular involvement Newer minimally invasive techniques emerging Stereotactic or endoscopic aspiration Role in therapy is unclear at this time Patients present with a sudden and severe headache Worse than any previous headache 50% lose consciousness 6-16% have seizures Diagnosis is confirmed by CT scan or MRI CT angiography required to locate a bleeding aneurysm Highest incidence of morbidity and mortality in the first 2 weeks Goal is prevention of secondary brain injury caused by Re-bleeding Vasospasm Delayed cerebral ischemia Principles of early medical management Airway management Cardiovascular support Lowering of blood pressure Reversal of anticoagulants ICP Control Prevention of vasospasm Surgical and endovascular interventions Ruptured aneurysms Should be performed as soon as possible Surgical clipping Endovascular coiling Microsurgery after failed endovascular attempt Un-ruptured aneurysms Intervention based on location and size of aneurysm Case by case intervention Evaluate the immediate risk versus benefit 8

9 Delayed cerebral ischemia (DCI) Several proposed mechanisms Vasospasm Microcirculatory dysfunction Loss of autoregulation Cortical spreading depolarization Micro-thrombosis Nimodipine for prevention of DCI Only FDA approved medication for prevention Landmark study shows significant reduction in cerebral infarction, poor neurological outcome, and death 1 1. Pickard JD, et al. Br Med J Nimodipine Cerebral-selective dihydropyridine calcium channel blocker Dosing: 60 mg orally every 4 hours for 21 days Available in 30 mg capsule and newer 3mg/ml oral solution Systemic hypotension is the main and limiting side effect Alternate regimens proposed for hypotensive patients 30 mg orally every 2 hours 15 mg orally every 1 hour Ongoing Study Clinical Trials.gov Nimodipine Microparticles to Enhance Recovery while Reducing Toxicity after (NEWTON) Prevention strategies Enhanced blood clearance Thrombolytic studies failed to show outcome benefit Avoid hypovolemia Isotonic crystalloid resuscitation to euvolemia is recommended Avoid hyponatremia Fludrocortisone mg/day provides some benefit 3% sodium chloride infusion has anecdotal benefits Prevention of DCI Vasospasm induced DCI 1 st line treatment 2 nd line treatment Refractory Experimental Interventions DCI Treatment Options Triple H therapy Hypertension, hypervolemia, and hemodilution Used since the 1980 s but has fallen out of favor Hypervolemia and hemodilution may cause harm Induced hypertension (SBP mmhg) Volume optimization targeting euvolemia Prevention of DCI Vasospasm induced DCI 1 st line treatment 2 nd line treatment Refractory Experimental Interventions Refractory DCI treatment Endovascular Therapy Balloon Angioplasty Intra-arterial Vasodilators (Verapamil) Cardiac Output Augmentation Cardiac Index >4 L/min/m 2 Hemoglobin Optimization Conflicting study results Aggressive transfusion to hemoglobin level g/dl Prevention of DCI Vasospasm induced DCI 1 st line treatment 2 nd line treatment Refractory Experimental Interventions Non-evidence based treatment Therapeutic hypothermia Goal systemic temperature 33-36ºC 23.4% Hypertonic saline bolus Simultaneous DCI with elevated ICP Intrathecal nicardipine Limited data from case studies and case series 4mg/4mL injection into the EVD 1 Aortic flow diversion Intra-aortic balloon pump counter-pulsation Prevention of DCI Vasospasm induced DCI 1 st line treatment 2 nd line treatment Refractory Experimental Interventions 1. Lu N et al. Neurocritical Care

10 Summary Stroke is a devastating disease with high mortality and morbidity if left untreated Ischemic stroke accounts for the majority of strokes and is caused by a clot in the brain whereas hemorrhagic stroke is caused by an arterial rupture Outcomes in ischemic stroke are improving rapidly as more therapies are being developed and more patients are receiving treatment IV fibrinolytic therapy remains the cornerstone of treatment in ischemic stroke New advances in endovascular therapy offer evidence based treatment for proximal arterial occlusions Summary Although hemorrhagic stroke accounts for a small percentage of strokes it carries a high morbidity and mortality Medical management of intracerebral hemorrhage focuses on prevention of hematoma expansion, IVH extension, ICP elevation, early blood pressure management, and anticoagulant reversal Medical management of subarachnoid hemorrhage focuses on prevention of delayed cerebral ischemia which is most likely caused by arterial vasospasm References References Alteplase package insert. US Food and Drug Administration. American Heart Association. Heart.org American Stroke Association. Strokeassociation.org Anderson CS, et al. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. N Engl J Med. 2016; 374: Anderson CS, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 2008;7: Anderson CS, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368: Berkhemer OA, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1): Bracard S, Ducrocq X, Mas JL. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomized controlled trial. Lancet Neurol. 2016;15(11): Campbell BC, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11): Chang P, Prabhakaran S. Recent advances in the management of acute ischemic stroke. F1000 Research. 2017; 6: 484. De Oliveira Manoel, et al. The critical care management of spontaneous intracranial hemorrhage: a contemporary review. Critical Care. 2016; 20:272. Francoeur CL, Mayer SA. Management of delayed cerebral ischemia after subarachnoid hemorrhage. Critical Care. 2016; 20:277. Frontera JA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care Feb;24(1):6-46. Grasso G, et al. Management of aneurysmal subarachnois hemorrhage: State of the art and future perspectives. Surg Neurol Int. 2017; 8:11. Goyal M, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11): Jovin TG, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24): Kang DH, Park J. Endovascular Stroke Therapy Focused on Stent Retriever Thrombectomy and Dircet Clot Aspiration: Historical Review and Modern Application. J Korean Neurosurg Soc. 2017; 60(3): Kim JY, Bae HJ. Spontaneous : Management. Journal of Stroke. 2017; 19(1): Lu N, et al. Intraventricular nicardipine for aneurysmal subarachnoid hemorrhage related vasospasm: assessment of 90 days outcome. Neurocritical Care Jun;16(3): Pena ID, et al. Strategies to Extend Thrombolytic Time Window for Ischemic Stroke Treatment: An Unmet Clinical Need. Journal of Stroke. 2017:19 (1): Pickard JD, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. Br Med J. 1989;298: References Politi M, et al. Endovascular Therapy for Acute Stroke. Prog Cardiovasc Dis Qureshi AI, et al. Effect of systolic blood pressure reduction on hematoma expansion, perihematomal edema, and 3-month outcome among patients with intracerebral hemorrhage: results from the antihypertensive treatment of acute cerebral hemorrhage study. Arch Neurol. 2010;67: Qureshi AI, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375: Rabinstein AA. Treatment of Acute Ischemic Stroke. Continuum Journal. 2017; 23(1): Rajah GB, Ding YD. Experimental neuroprotection in ischemic stroke: a concise review. Neurosurg Focus. 2017; 42(4): E2. Saver JL, et al. Stent-retriever thrombectomy after intravenous t-pa vs. t-pa alone in stroke. N Engl J Med. 2015;372(24): Stern GM, et al. Thrombolytic Therapy in Wake-Up Stroke Patients. Clinical Neuropharmacology. 2017; 40(3): FSHP Contemporary Therapeutics of Stroke Management Cardiovascular Track Daniel A. Jackson, Pharm.D., BCPS Mayo Clinic in Florida 10