Jointly provided by Potomac Center for Medical Education and Rockpointe Supported by an educational grant from Genentech, A Member of the Roche Group

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1 Jointly provided by Potomac Center for Medical Education and Rockpointe Supported by an educational grant from Genentech, A Member of the Roche Group

2 Faculty Speakers Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC Executive Director of Interventional Cardiovascular Programs Brigham and Women s Hospital Heart & Vascular Center Professor of Medicine, Harvard Medical School Boston, MA Lee H. Schwamm, MD, FAHA Executive Vice Chairman, Department of Neurology C. Miller Fisher Chair and Chief of MGH Stroke Services Professor of Neurology, Harvard Medical School Boston, MA

3 Disclosures Faculty The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC: Research: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company Lee H. Schwamm, MD, FAHA: Research: Genentech, Lundbeck, Medtronic, Penumbra Non-faculty Content Contributors Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Barry Watkins, PhD; Blair St. Amand; Jay Katz, CCMEP; Ashley Marostica: Nothing to disclose

4 Educational Objectives Analyze the strength of the clinical data that relate to the efficacy and safety of fibrinolytic therapy, including survival, quality-of-life outcomes, and hemorrhagic complications Discuss quality improvement initiatives focused on improving acute ischemic stroke care by reducing event-to-ed-door and door-to-needle times for eligible patients being treated with fibrinolytic therapy

5 Introduction With rapid, aggressive prehospital stroke care, at-risk patients can be appropriately managed and quickly assessed for fibrinolytic therapy that may significantly improve their outcomes. American Heart Association s Advanced Cardiac Life Support: Principles and Practice; Chapter 18: Acute Stroke: Current Treatments and Paradigms.

6 Improving Stroke Outcomes Current guidelines for the management of patients with acute ischemic stroke published by the AHA/ASA include specific recommendations for the administration of IV t-pa Despite its effectiveness in improving neurological outcomes, many patients with ischemic stroke are not treated with t-pa, because they arrive late or because of delays in assessment/administration of IV t-pa Earlier administration of IV t-pa after the onset of stroke symptoms is associated with greater functional recovery One of the potential approaches to increase treatment opportunities and improve stroke outcomes is to provide this treatment in a more timely fashion after patient arrival (reduce the door-to-needle time for IV t-pa) Fonarow GC et al. Stroke. 2011;42:

7 Primary t-pa Data NINDS 1995 t-pa Given within 3 Hours after Acute Stroke t-pa Placebo Time to Treatment after Stroke Onset Number of Patients Number with Improvement (%) Number of Patients Number with Improvement (%) Relative Risk (95% CI) P Value 0-90 minutes (55%) (42%) 1.3 ( ) minutes (39%) (37%) 1.1 ( ) minutes (47%) (39%) 1.2 ( ) 0.06 NINDS. N Engl J Med. 1995;333:

8 Number Needed to Treat To Benefit from Intravenous t-pa across Full Range of Functional Outcomes Outcome NNT Normal/Near Normal 8.3 Improved 3.1 For every 100 patients treated with t-pa, 32 benefit, 3 harmed Saver JL. Stroke. 2007;38:

9 Primary t-pa Data NINDS 1995 t-pa Given within 3 Hours after Acute Stroke Time to Treatment after Stroke Onset t-pa Placebo Relative Risk (95% CI) P Value 0-90 minutes (n = 157) (n = 145) Modified Rankin scale Glasgow outcome scale NIHSS score minutes (n = 155) (n = 167) Modified Rankin scale <0.001 Glasgow outcome scale , HIHSS score NINDS. N Engl J Med. 1995;333:

10 Primary t-pa Data NINDS 1995 t-pa Given within 3 Hours after Acute Stroke Type of Intracranial Hemorrhage t-pa (n = 312) Placebo (n = 312) Symptomatic 20 (6.4%) 2 (0.6%) Asymptomatic 14 (4.5%) 9 (2.9%) Survival rate (3 mo) 87.2% 79.5% NINDS. N Engl J Med. 1995;333:

11 Clinical Outcomes in Ischemic Stroke Patients Door-to Needle (DTN) Time <60 Min. Versus DTN Time >60 Min. Events; Status DTN < 60 min DTN > 60 min p In-Hospital Mortality 8.6% 10.4% < Ambulatory Status Able 40.2% 39.6% With assistance 29.8% 30.1% Not able 22.0% 22.5% Not documented 2.0% 2.0% t-pa Complications Any 8.0% 9.0% Systemic intracranial hemorrhage 4.7% 5.6% Life threatening/serious hemorrhage 1.2% 1.5% Other complication 1.2% 1.0% Fonarow GC et al. Circulation 2011;123:

12 Effects of t-pa on Outcomes at Final Follow-up All deaths between 7 days and final follow-up All deaths Alive and independent (mrs 0-2) Trials Events/patients rt-pa Control Odds ratio (95% CI) All trials before IST / / ( ) IST / / ( ) All trials 8 323/ / ( ) P=0.03 All trials before IST / / ( ) IST / / ( ) All trials / / ( ) P=0.33 All trials before IST / / ( ) IST / / ( ) All trials / / ( ) P=0.001 All trials before IST / / ( ) Favorable outcome (mrs 0-1) IST / / ( ) All trials 8 323/ / ( ) P< mrs = modified Rankin Score Thrombolysis Thrombolysis Wardlaw JM et al. Lancet. 2012;379: decreases increases

13 Fibrinolytic Therapy for Ischemic Stroke Intravenous t-pa represents the first FDA-approved therapy for acute ischemic stroke In the NINDS trial, patients treated with t-pa within 3 hours of onset of symptoms were at least 30% more likely to have minimal or no disability at 3 months compared with placebo Careful patient selection and strict adherence to treatment protocol is essential American Heart Association s Advanced Cardiac Life Support: Principles and Practice; Chapter 18: Acute Stroke: Current Treatments and Paradigms.

14 Prehospital Triage for Suspected Acute Stroke Site of stroke ALS transport BLS transport Air transport Is this telestroke? Coming soon to a curb near you? T-PA Onsite

15 Fibrinolytic Therapy for Ischemic Stroke There were 10-fold increases in the risk of fatal intracranial hemorrhage in the treated group (3% vs 0.3%) and the frequency of all symptomatic hemorrhage (6.4% vs 0.6%) This increase in symptomatic hemorrhage did not lead to an overall increase in mortality in the treated group Symptomatic ICH rates in subsequent trials and in real world practice have continued to decrease to <5% American Heart Association s Advanced Cardiac Life Support: Principles and Practice; Chapter 18: Acute Stroke: Current Treatments and Paradigms.

16 Number of Patients Who Benefit and Are Harmed per 100 Patients Treated with t-pa Lansberg MG et al. Stroke. 2009;40:

17 t-pa Given within 3 Hours after Acute Stroke Disability Scores and Survival at 6 and 12 Months Time Point; Assessment Score / Survival t-pa (n = 312) Placebo (n = 312) Odds Ratio Relative Risk P value 6-month Global test 1.7 < month Barthel index month Modified Rankin scale month Glasgow Outcome scale month Survival 79.5% 76.6% NS 12-month Global test month Barthel index month Modified Rankin scale month Glasgow Outcome scale month Survival 75.6% 72.4% NS Kwiatkowski TG et al. N Engl J Med. 1999;340:

18 Management of Acute Ischemic Stroke Quality Improvement: Reducing Door-to-Needle Time

19 Acute Stroke Management Issues for Neuro-intervention Sequential timing metrics Management strategy dependent on severity Expedited decision-making Minimizing time to treatment Redefining outcomes measures Sun C-H J et al. Circulation. 2014;129:

20 Seven-step Stroke Chain of Survival and Recovery Before Hospital Arrival Detection Dispatch Delivery After Hospital Arrival Door Data Decision Drug American Heart Association s Advanced Cardiac Life Support: Principles and Practice; Chapter 18: Acute Stroke: Current Treatments and Paradigms.

21 Acute Stroke Management: Sequential Timing Metrics Last known normal EMS contact; call 911 EMS notification of primary stroke center EMS arrival to primary or comprehensive stroke center Image acquisition and interpretation Determine eligibility for acute thrombolytic therapy Treatment Initiation Adapted from Sun C-H J et al. Circulation. 2014;129:

22 Prehospital Care Stroke education Call 911 Prehospital assessment tools Field management Rapid transport to stroke center Prehospital notification The Bottom Line: Focus on limiting delays and recognize that interhospital transfers of acute stroke patients for higher-level care are increasingly common

23 Best Practices to Shorten Event-Door Time Hospital pre-notification by Emergency Medical Services Rapid triage protocol and stroke team notification Single call/paging activation system for entire stroke team Fonarow GC et al. Target: Stroke initiative. Stroke. 2011;42(10):

24 Best Practices to Shorten Door-Needle Time Use of a stroke toolkit containing clinical decision support, strokespecific order sets, guidelines, hospital-specific algorithms, critical pathways, NIH Stroke Scale and other stroke tools Rapid acquisition and interpretation of brain imaging Rapid laboratory testing (including point-of-care testing) if indicated Pre-mixing t-pa medication for high likelihood candidates Rapid access to intravenous t-pa in the ED/brain imaging area Team-based approach Rapid data feedback to stroke team on each patient s DTN time and other performance data Fonarow GC et al. Target: Stroke initiative. Stroke. 2011;42(10):

25 Thrombolytic Therapy Checklist Eligibility Criteria >18 years of age with ischemic stroke 3 hours Stroke deficit assessment Deficit found to be potentially disabling Severity quantified with NIH stroke scale (0-42 scale) (Stroke scale training available at: Coagulation status No evidence of coagulopathy, if tested: INR <1.8 and normal PT if taking warfarin, INR <1.8 Platelets >100,000 Blood pressure: SBP <185 mm Hg, DBP <110 mm Hg Glucose >50 mg/dl Updated from Adams HP et al. ASA Stroke Council. Stroke. 2003;34:

26 Emergency Department-based 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 minutes 15 minutes 25 minutes 45 minutes 60 minutes 3 hours Jaunch EC et al. Stroke. 2013;44:

27 Estimated Odds Ratio (+ 95%CI) for Favorable 3-month Outcome in t-pa Treated Acute Stroke Patients Compared to Placebo Marler JR et al. Neurology. 2000;55: With permission from Wolters Kluwer Health, Inc.

28 Target: Stroke Initiative Conclusions The timeliness of t-pa administration improved substantially in GWTG Stroke Hospitals after initiation of the multidimensional AHA/ASA Target: Stroke quality initiative The proportion of patients with DTN times <60 minutes increased from 29.6% to 53.3%; there was also a more than 4-fold increase in annual rate of improvement in patients with DTN times <60 min More rapid perfusion therapy in acute ischemic stroke is not only feasible, but can be achieved with actual reductions in complications and improved outcomes Fonarow GC et al. JAMA. 2014;311:

29 Endovascular Embolectomy Devices Preliminary Clinical Trial Data IMPROVED INTRA-ARTERIAL MECHANICAL EMBOLECTOMY DEVICES* MR CLEAN Various embolectomy devices Functional benefits: lower modified Rankin Scale score ESCAPE Various embolectomy devices Functional benefits: early termination interim analysis showing benefit EXTEND IA Solitaire FR device Functional benefits: early termination interim analysis showing benefit SWIFT Solitaire FR device versus Merci device Solitaire had superior functional benefit, triggering early termination of study SWIFT PRIME Solitaire FR device Solitaire FR had superior 90-day functional benefit; DSMC recommended to suspend patient recruitment * Commonly evaluated in patients given prior thrombolysis

30 GWTG-Stroke Participating Hospitals Registry Data on Door-to-Needle (DTN) Time and Clinical Outcomes PERFORMANCE MEASURES PRE-INTERVENTION (n = 27,319) POST-INTERVENTION (n = 43,850) ODDS RATIO P VALUE tpa DTN time <60 min 26.5% 41.3% <0.001 In-hospital all-cause mortality 9.93% 8.25% 0.89 <0.001 Discharge to home 37.6% 42.7% 1.14 <0.001 Independent ambulatory status 42.2% 45.4% Symptomatic intracranial hemorrhage within 36 hours 5.68% 4.68% 0.83 <0.001 Fonarow GC et al. JAMA. 2014;311:

31 Proportion DTN <60 Minutes Time Trend in the Proportion of Patients with Door-to-Needle Times within 60 Minutes Before and After Initiation of Target: Stroke (P< for comparison of the two slopes) Target: Stroke Initiation Fonarow GC et al. JAMA. 2014;311: Time (Quarter / Year)