ENCHANTED Era: Is it time to rethink treatment of acute ischemic stroke? Kristin J. Scherber, PharmD, BCPS Emergency Medicine Clinical Pharmacist

Transcription

1 ENCHANTED Era: Is it time to rethink treatment of acute ischemic stroke? Kristin J. Scherber, PharmD, BCPS Emergency Medicine Clinical Pharmacist Pharmacy Grand Rounds 26 July MFMER slide-1

2 Learning Objectives: Recall the pathophysiology of acute ischemic stroke. Explain the mechanism of action of alteplase in the treatment of acute ischemic stroke. Review the evidence supporting the use of alteplase in the treatment of acute ischemic stroke. Discuss the recently published ENCHANTED trial to guide recommendations in an acute ischemic stroke patient case MFMER slide-2

3 Stroke Epidemiology Nearly 795,000 Americans suffer a stroke annually An estimated 6.4 per 100,000 children (age 0-15 years) 5 th leading cause of death in the United States 130,000 people per year Leading cause of long-term disability American Heart Association/ American Stroke Association MFMER slide-3

4 Visual field deficit Paralysis Aphasia Gaze deviation Sensory loss Dysarthria Eye movement Neglect Acute Onset Prabhakaran S, et al. JAMA. 2015;313(14): MFMER slide-4

5 Ischemic 85% Hemorrhagic 15% Thrombosis Systemic Hypoperfusion Embolic Large Vessel Small Vessel Arterial Unknown source Cardioembolic Prabhakaran S, et al. JAMA. 2015;313(14): MFMER slide-5

6 Ischemic Core Ischemic Penumbra Prabhakaran S, et al. JAMA. 2015;313(14): MFMER slide-6

7 Question 1: The ischemic penumbra is defined as: 1) Infarcted tissue 2) Tissue at risk for permanent infarction 3) Normally perfused brain tissue 4) Area surrounding a stenotic blood vessel 2015 MFMER slide-7

8 How do we evaluate for stroke? 2015 MFMER slide-8

9 History and Physical Establish clear time of onset Rule out stroke mimics Seizures Syncope Migraine Hypoglycemia Drug toxicity Concurrent medications Anticoagulants Jauch EC, et al. Stroke. 2013;44 (3): MFMER slide-9

10 Neurological Exam National Institutes of Health Stroke Scale (NIHSS) Stroke Scale Stroke Severity 0 No stroke 1-4 Minor stroke 5-15 Moderate stroke 6-20 Moderate to severe stroke Severe stroke National Institutes of Health 2015 MFMER slide-10

11 Exam Continued Neuroimaging Non-contrast brain CT or brain MRI Laboratory parameters Blood glucose* CBC with platelets PT and INR, aptt Serum electrolytes, cardiac biomarkers ECG Oxygen saturation Jauch EC, et al. Stroke. 2013;44 (3): MFMER slide-11

12 ED Based Stroke Care Action Door to physician Door to stroke team Door to CT initiation Door to CT interpretation Door to drug ( 80% compliance) Door to stroke unit admission Time 10 min 15 min 25 min 45 min 60 min 3 hours Jauch EC, et al. Stroke. 2013;44 (3): MFMER slide-12

13 How do we treat ischemic stroke? 2015 MFMER slide-13

14 Genentech. Cathflo. Accessed 7/18/ MFMER slide-14

15 Question 2: Alteplase exerts its mechanism of action by: 1) Inhibition of thromboxane A2 on platelets leading to decreased platelet aggregation 2) Antithrombin III mediated inhibition of thrombin and anti-xa 3) Direct inhibition of thrombin 4) Fibrin enhanced conversion of plasminogen to plasmin 2015 MFMER slide-15

16 Trial Year N Drug Time to Treatment Outcome MAST Italy Streptokinase < 6 hours Death, 6 mo. Summary of stroke trials ECASS I Alteplase (1.1 mg/kg) < 6 hours disability or death NINDS Alteplase (0.9 mg/kg) < 3 hours No Δ 24 hr NINDS Alteplase (0.9 mg/kg) < 3 hours MAST Europe * Streptokinase < 6 hours ASK * Streptokinase < 4 hours 30% more likely no/minimal 3 mo. NNT = 8 Harm due to ICH Stopped early 3 mo. No difference disability Stopped early ECASS II Alteplase (0.9 mg/kg) < 6 hours (20% < 3 hrs) disability at 3 mo. ATLANTIS B * Alteplase (0.9 mg/kg) 20% 3 4 hr, 70% 4 5 hr Harm due to ICH Stopped early Key Harm No benefit Benefit ATLANTIS A * Alteplase (0.9 mg/kg) < 6 hours ECASS III Alteplase (0.9 mg/kg) hours DIAS Desmoteplase 3 9 hours disability ICH, death at 3 mo. Stopped early Improved functional outcomes at 3 mo. NNT = 15 IST Alteplase (0.9 mg/kg) < 6 hours % alive, 6 mo. DIAS Desmoteplase 3 9 hours 3 mo MFMER slide-16

17 NINDS: 0.9 mg/kg alteplase vs placebo Part 1 (N = 291) Primary outcome: improvement of NIHSS 4 within 24 hours Part 2 (N = 333) Primary outcome: clinical improvement at 3 months using global outcome analysis Barthel index (BI) Modified Rankin scale (mrs) Glascow outcome scale NIHSS NINDS rt-pa Stroke Study Group.. N Engl J Med Dec 14;333(24) 2015 MFMER slide-17

18 NINDS Results Odds Ratio Alteplase Placebo (95% CI) Primary Outcome % Favorable outcome at 90d Relative Risk (95% CI) P Value Global test 1.7 ( ) BI ( ) 1.3 ( ) mrs ( ) 1.5 ( ) Glascow outcome scale ( ) 1.4 ( ) NIHSS ( ) 1.5 ( ) Secondary Outcome N (%) SICH 20 (6.4) 2 (0.6) < 0.01 Mortality at 90d 54 (17) 64 (21) 0.30 NINDS rt-pa Stroke Study Group.. N Engl J Med Dec 14;333(24) 2015 MFMER slide-18

19 ECASS III The 3 to 4.5 hour window Alteplase (N = 418) Placebo (N = 403) Odds Ratio (95% CI) P Value N (%) Primary endpoint Disability at 90d (mrs 0 or 1) 219 (52.4) 182 (45.2) 1.34 ( ) 0.04 Secondary endpoint SICH 33 (7.9) 14 (3.5) 2.38 ( ) Mortality at 90d 32 (7.7) 34 (8.4) 0.90 ( ) 0.68 Hacke, W., et al. N Engl J Med. 2008; 359: MFMER slide-19

20 Question 3: Based on the results of the ECASS III trial, the FDA has approved alteplase for the treatment of acute ischemic stroke in select patients within 3 to 4.5 hours after symptom onset. 1) True 2) False 2015 MFMER slide-20

21 American Heart Association (AHA) and American Stroke Association (ASA) Acute Ischemic Stroke Guidelines 2013 Alteplase (0.9 mg/kg, maximum dose 90 mg) for select patients treated within 3 hours Class I; Level of evidence A Door to needle time < 60 minutes Alteplase for select patients treated in 3 to 4.5 hours Class I; Level of evidence B Jauch EC, et al. Stroke. 2013;44 (3): MFMER slide-21

22 Inclusion Criteria Measurable neuro deficit Age 18 y No evidence of ICH on CT Onset < 3 hours Exclusion Criteria Head trauma, prior stroke in last 3 mo. Symptoms suggestive of SAH Hx ICH Intracranial neoplasm, AVM, aneurysm Recent intracranial, spine surgery HTN (SBP > 185, DBP > 110) Active bleeding Plts < 100k UFH w/in 48 hr, aptt > ULN INR > 1.7, PT > 15 sec. Current use DTIs, Xa inhibitors Blood glucose < 50 mg/dl CT = hypodensity > 1/3 cerebral hemisphere Jauch EC, et al. Stroke. 2013;44 (3): MFMER slide-22

23 AHA/ASA 2013 Guidelines AHA/ASA 2016 Update Inclusion Criteria Measurable neurological deficit Onset of symptoms within 3 to 4.5 hours before treatment Exclusion Criteria Age > 80 years Severe stroke (NIHSS > 25) Severe stroke (NIHSS > 25) History of oral anticoagulation use regardless of INR History of warfarin use and an INR > 1.7 History of both diabetes and prior stroke Jauch EC, et al. Stroke. 2013;44 (3): Demaerschalk BM, et al. Stroke. 2016;47(2): ; 2015 MFMER slide-23

24 What is the risk of symptomatic ICH (SICH)? Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register N = 31,627 recipients of IV alteplase Overall rate of SICH = 1.8% using SITS-MOST definition Mazya M, et al. Stroke. 2012;43: MFMER slide-24

25 Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. Anderson CS, et al. N Engl J Med. 2016; 374: For the ENCHANTED investigators 2015 MFMER slide-25

26 ENCHANTED: Population: age > 18 years, able to receive thrombolysis with 4.5 hours, baseline mrs of 0 or 1, SBP 185 mmhg Intervention: Alteplase 0.6 mg/kg Control: Alteplase 0.9 mg/kg Outcome (primary): combined endpoint of death or disability at 90 days (mrs = 2-6) Outcome (secondary): ICH using SITS-MOST definition Anderson CS, et al. N Engl J Med. 2016; 374: MFMER slide-26

27 Statistical Analysis Unadjusted logistic regression model to test non-inferiority Upper boundary of 95% CI for odds ratio of low-dose compared to standard dose had to fall below a margin of 1.14 Sample size 3300 patients 90% power to detect non-inferiority 80% power to detect superiority of low-dose in achieving 40% lower risk of ICH Anderson CS, et al. N Engl J Med. 2016; 374: MFMER slide-27

28 Results Low Dose Alteplase N = 1654 Standard Dose Alteplase N = 1643 Odds Ratio (95% CI) P Value P Value for Non inferiority Death or Disability (mrs = 2 6) at 90 days SICH by SITS MOST SICH by NINDS 53.2% (855/1607) 1% (17) 5.9% (98) Primary Outcome 51.1% (817/1599) 1.09 (0.95 to 1.25) Secondary Outcomes 2.1% 0.48 (35) (0.27 to 0.86) 8% 0.73 (131) (0.55 to 0.95) Death within 90 days 8.5% (140) 10.3% (170) 0.8 (0.63 to 1.01) 0.07 Anderson CS, et al. N Engl J Med. 2016; 374: MFMER slide-28

29 Authors Conclusions Death or disability Low dose alteplase NOT non-inferior to standard dose SICH Less bleeding in low dose group Mortality at 90 days No difference Anderson CS, et al. N Engl J Med. 2016; 374: MFMER slide-29

30 ENCHANTED Strengths Large study Clinically relevant question Important patient centered outcomes Assessors of outcomes were blinded Minimal loss to follow-up Limitations Open label design Co-primary endpoint Baseline NIHSS score = 8 Consecutive recruitment? Asian descent > 60% Mixed follow-up collection methods (in person vs phone) Anderson CS, et al. N Engl J Med. 2016; 374: MFMER slide-30

31 Patient Case - BL 72 yo Caucasian Female Presents to ED after sudden onset facial droop and left arm weakness Last normal 2 hours prior to presentation PMH: HTN, CAD, osteoporosis Home meds: lisinopril, metoprolol, atorvastatin, ASA, clopidogrel, acetaminophen 2015 MFMER slide-31

32 Patient BL Continued Baseline NIHSS = 13 Non-contrast CT brain = no ICH Blood glucose = 110 mg/dl Current BP = 165/95 mmhg SITS-SICH = 8 (moderate risk) 2015 MFMER slide-32

33 Question 4: Based on the results of the ENCHANTED trial, what treatment option would you offer to this patient? 1) Standard dose Alteplase 2) Low dose Alteplase 3) No lytic therapy 2015 MFMER slide-33

34 Summary Acute ischemic stroke is most commonly caused by occlusion of an artery leading to decreased cerebral perfusion. Alteplase exerts its mechanism of action by binding to fibrin, leading to activation of plasminogen to plasmin and local fibrinolysis. After receiving alteplase, subjects in NINDS-2 and ECASS III showed improvement in functional outcomes at 90 days. ENCHANTED did not meet non-inferiority for low versus standard dose alteplase MFMER slide-34

35 Questions & Discussion 2015 MFMER slide-35

36 Trial Publication Design MAST Italy ECASS I Lancet Dec 9;346(8989): JAMA Oct 4;274(13): Randomized, 2x2 factorial (streptokinase, ASA, placebo, strep+asa) Randomized, prospective, multicenter, double blind, placebocontrolled Number of Patients Drug Time to Treatment 622 Streptokinase < 6 hours 620 Alteplase (1.1 mg/kg) < 6 hours Results Outcome Increased early death (OR 2.7), slight decrease in No benefit disability at 6 months (OR 0.5) No difference in disability or death No benefit NINDS 1 Randomized, N Engl J Med. prospective, 1995 Dec multicenter, 14;333(24):1581 double blind, 7. placebocontrolled 291 Alteplase (0.9 mg/kg) < 3 hours No difference in improvement of NIHSS scale by 4 pts or resolution of deficits at 24 hours No benefit NINDS 2 Randomized, N Engl J Med. prospective, 1995 Dec multicenter, 14;333(24):1581 double blind, 7. placebocontrolled 333 Alteplase (0.9 mg/kg) < 3 hours Lytic recipients were 30% more likely to have minimal or no disability at 3 months. Increased ICH 6.4% vs 0.6% (p<0.001). No difference in mortality. NNT = MFMER slide-36

37 Trial Publication Design MAST Europe ASK ECASS II N Engl J Med Jul 18;335(3): JAMA Sep 25;276(12): Randomized, prospective, multicenter, double blind, placebocontrolled Randomized, prospective, multicenter, double blind, placebocontrolled Randomized, prospective, Lancet Oct multicenter, 17;352(9136):12 double blind, placebocontrolled Number of Patients Drug Time to Treatment 310* Streptokinase < 6 hours 340* Streptokinase < 4 hours 800 Alteplase (0.9 mg/kg) < 6 hours (20% < 3 hrs) Results Outcome No difference combined disability/death at 6 months, increased ICH, Harm, stopped statistically nonsignificant early increased mortality at 6 months No difference combined disability/death at 3 months, slightly Harm, stopped decreased early disability and increased mortality at 3 months, OR 1.83 ( ) No difference in favorable outcomes (modified Rankin Scale) at 3 months No benefit 2015 MFMER slide-37

38 Trial Publication Design DIAS 2 Randomized, prospective, Lancet Neurol. dose ranging, 2009 double blind, Feb;8(2): placebocontrolled Number of Patients Drug Time to Treatment 193 Desmoteplase 3 9 hours Results Outcome No difference in favorable outcomes, statistically nonsignificant No benefit increase in mortality for high dose desmoteplase group IST 3 Lancet Jun 23;379(9834): Randomized, prospective, multicenter, open label, placebocontrolled 3055 Alteplase (0.9 mg/kg) < 6 hours Short term mortality increase of 4% in first 7 days (lytic recipients), no difference in No benefit primary outcome (% alive and independent at 6 months). DIAS 3 Lancet Neurol Jun;14(6): Randomized, prospective, multicenter, parallel group, placebocontrolled 492 Desmoteplase 3 9 hours No difference in favorable outcomes (modified Rankin Scale) at 3 months No benefit 2015 MFMER slide-38

39 Blood pressure control Before lytic therapy SBP 185 mmhg, DBP 110 mmhg After lytic therapy BP 180/105 mmhg for first 24 hours No lytic therapy Permissive HTN Treat if SBP > 220 mmhg, DBP > 120 mmhg Jauch EC, et al. Stroke. 2013;44 (3): MFMER slide-39

40 Disability assessment scales Barthel Index: assessment of ability to perform ADLs. Score of 100 = total independent. Modified Rankin scale: 0 = normal, 5 = severe disability Glascow outcome scale: 1 = good recovery, 2 moderate disability, 3 severe disability, 4 survival but vegetative state, 5 death NIHSS: quantifies neurologic deficits in 11 categories. 0 = normal, no deficit MFMER slide-40

41 Cochrane Review 2014 Included 27 trials. N = 10,187 Most data comes from trials allowing treatment up 6 hours after onset Results Odds Ratio (95% CI) Death or disabled (mrs of 3 to 6) at 3 6 mo ( ) SICH 3.75 ( ) Early death (< 7d) 1.69 ( ) Death at 3 6 mo ( ) Wardlaw JM, et al. Cochrane Database of Systematic Reviews. 2014;(7): CD MFMER slide-41