Vallabh Janardhan, MD

Director, Texas Stroke Institute

Director, Comprehensive Stroke Program and Neuro-

Interventional Services, HCA North Texas Division

Natural history of acute stroke

from large vessel occlusion:

Results from the FIRST trial

Presenter Disclosure

FIRST Trial, Penumbra, Inc: Speakers Bureau

Principal Investigator

Data Safety Monitoring Board Member, Penumbra Pivotal Trial, Penumbra Inc.,

Consultant

Board Member, Insera Therapeutics Inc.,

Stocks/Stock Options

National Science Foundation Grant #0946099

Principal Investigator

FIRST Trial: Results 1

FIRST Cohort: Comparison with IMS 3

2

FIRST Cohort: Lessons learned about Infarct Core 3

Overview

FIRST Trial: Team 4

FIRST Trial: Results

FIRST Trial: Purpose

Termination of the IMS 3 trial due to futility has

led to further controversies surrounding the use

of IA endovascular therapy for stroke

intervention

Objective:

To assess the natural history of a stroke cohort

eligible for IA intervention and compare its

outcome with the IMS 3 results

Methods

Prospective, single arm, multi-center natural history study of a stroke cohort with the following inclusion criteria:

Large vessel occlusion

Present within 8 hours from symptom onset

Baseline NIHSS score ≥ 10

Ineligible or refractory to lytic therapy

Untreated with endovascular therapy

Interim analysis from 93 patients meeting study criteria

Primary endpoint is functional outcome at 90 days as defined by mRS 0-2

Participating Centers, Statistical Lab,

and Imaging Core Lab

Center Principal Investigator

Medical Center of Plano

Plano, TX, USA Vallabh Janardhan, MD

Plaza Medical Center

Plaza, TX, USA Vallabh Janardhan, MD

Prince of Wales Hospital

Hong Kong, China Thomas WH Leung, MD

Queen Mary Hospital

Hong Kong, China Raymond Cheung, MD, PhD

Personnel Location

Nam Nguyen (Statistical Lab) Chicago, IL

Albert Yoo, MD (Imaging Core Laboratory)

MGH/Harvard

Medical School,

Boston, MA

Target Vessel Location

MCA

ICA

ACA

Other

N=64/93

68.8%

N=1/93

1.1%

N=27/93

29.0%

N=1/93

1.1%

FIRST Baseline Characteristics

Patients (N) 93

Age (years) [mean/(SD)] 68.9 ± 14.9

Female 59.1% (55/93)

NIHSS [median/(IQR)] 18.0 (14.0-23.0)

TIMI 0-1 100% (93/93)

TICI 0-1 100% (93/93)

Refractory to IV rtPA 51.6% (48/93)

Results: Recanalization

0%

20%

40%

60%

80%

100%

TICI TIMI

TICI/TIMI 0-1 TICI 2a-3, TIMI 2-3

0%

20%

40%

60%

80%

100%

TICI TIMI

TICI/TIMI 0-1 TICI 2a-3, TIMI 2-3

BASELINE SPONTANEOUS

RECANALIZATION

100%

(93/93)

100%

(93/93)

11.1%

(6/54) 13.0%

(7/54)

Safety Results

Event Rate

All-Cause Mortality 39.8% (37/93)

All SAEs within 24 hrs of

stroke onset 26.9% (25/93)

Event Rate

Symptomatic ICH 5.4% (5/93)

Asymptomatic ICH 16.1% (15/93)

Total ICH 21.5% (20/93)

*29 events in 25 patients

Summary of SAEs within 24 hrs of Stroke Onset

Event % (n/N)

Cerebral Edema 7.5% (7/93)

Herniation Syndrome 1.1% (1/93)

Sequelae of CVA 4.3% (4/93)

Seizures 1.1% (1/93)

Respiratory Failure 6.5% (6/93)

Other Non-neurologic SAE 10.8% (10/93)

*29 events in 25 patients

Outcomes

Good Neurological Outcome % (n/N)

Discharge/7-Day NIHSS 0-1 or

10 point improvement 18.3% (17/93)

Good Outcome at 90 Days % (n/N)

mRS 0-2 15.6% (14/90)

Outcome: Patients refractory to IV

tPA vs. Patients ineligible for IV tPA

Refractory to IV tPA

N=48

Ineligible for IV tPA

N=45

Recanalization 20.0% (6/30) 4.2% (1/24)

ICH (within 24 hrs) 16.7% (8/48) 15.6% (7/45)

Mortality 33.3% (16/48) 46.7% (21/45)

Discharge/7-Day NIHSS 0-1

or 10 point improvement 22.9% (11/48) 13.3% (6/45)

90-day mRS 0-2 21.7% (10/46) 9.1% (4/44)

FIRST Cohort: Comparison with IMS 3

FIRST, IMS III, and Penumbra

Study Entry Criteria

FIRST IMS III Penumbra

Time from Onset ≤ 8 hours ≤ 3 hours ≤ 8 hours

IV rtPA Eligible? Ineligible or refractory Yes Yes

Age 18-85 18-82 18-85*

Baseline NIHSS ≥ 10 ≥ 10** ≥ 8

CTA Defined Large

Vessel Occlusion Required Optional Required

IA Therapy None Other IA

devices/IA tPA

Penumbra

System only

*Pivotal>18, START 18-85, RetroSTART, PICS, and POST no age criteria **Or NIHSS score 8-9 with CTA evidence of occlusion in M1, ICA, or BA

FIRST, IMS 3, and Penumbra

Baseline Characteristics

FIRST IMS 3 IV IMS 3 IV/IA Penumbra

Patients (N) 93 222 434 942

Age (years) [mean] 69 68 69 65

Female 59.1% 45.0% 49.8% 50.9%

NIHSS [median/IQR] 18 (14-23) 16 (8-30) 17 (7-40) 17 (13-21)

ASPECTS 8-10 50.5% 59.0% 56.9% 55.1%

FIRST, IMS 3, and Penumbra

Outcomes

FIRST

(N=93)

IMS 3 IV

(N=222)1

IMS 3 IV/IA

(N=434)1,2

Penumbra

(N=942)

TICI 2-3 13.0% 34.8%** 76.0%** 83.2%**

sICH 5.4% 5.9% 6.2% 12.6%*

Mortality 39.8% 21.6%** 19.1%** 21.7%**

90-Day mRS 0-2 15.6% 38.7%** 40.7%** 38.3%**

1Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular Therapy after Intravenous t-PA versus t-

PA Alone for Stroke. N Engl J Med 2013;368:893-903. 2Tomsick TA, IMS III Investigators. IMS III: Comparison of Outcome by IA Approach and Interpretation

in Light of Comparative Trials. In: International Stroke Conference; Honolulu, Hawaii; 2013.

*P<0.05; **P<0.01 compared to FIRST, Fisher’s Exact two-sided test

Discussion

Large vessel acute ischemic stroke is a

malignant disease wherein 81.7% of patients will

either die or suffer long-term disabilities if

untreated (81.7% at 7 days; 84.4% at 90 days).

Endovascular therapy for large vessel occlusion

is safe and effective when compared to

medical therapy in an appropriate stroke

cohort ineligible or refractory to IV rtPA

FIRST Cohort: Lessons learned about

Infarct Core

Importance of Core Infarct Volume in

the Number Needed to Treat

Infarct core has been theorized to be an

important indicator for treatment success from

endovascular intervention in acute ischemic

stroke from large vessel proximal occlusion.

Objective:

To determine the extent to which it contributes to

the number of patients needed to treat (NNT) to

achieve long-term functional independence.

Zaidat O, Yoo A, Janardhan V, Frei D, Ammar L, Meyer D, To C, Kuo SS, Buell H, Barraza L, Bose A, Sit SP. The Importance of Core Infarct Volume in

the Number Needed to Treat in Endovascular Therapy for Acute Ischemic Stroke. Presented at SNIS, Colorado Springs, CO, July 2014.

Patients pooled from various trials

Patients treated by the Penumbra System with acute stroke not

eligible and/or refractory to IV rtPA were pooled from numerous

trials (N=463) and compared with 93 control patients who were

eligible for but not treated by endovascular therapy.

PICS

RetroSTART

START

Pivotal

N=174/463

37.6%

N=96/463

20.7%

N=83/463

17.9%

N=110/463

23.8%

ASPECTS Distribution

Small

Medium

Large

N=257/463

55.5% N=155/463

33.5%

N=51/463

11.0%

N=29/84

34.5%

N=41/84

48.8%

N=14/84

16.7%

Note: 9 control patients did not have ASPECTS score.

CONTROL (N=93) PENUMBRA (N=463)

Outcomes Control (N=93) and Penumbra System (N=463)

TIMI 2-3 % (n/N)

sICH % (n/N)

Mortality % (n/N)

90-Day mRS 0-2 % (n/N)

Control Penumbra Control Penumbra Control Penumbra Control Penumbra

Overall 12.0% (6/50)

81.7%*** (376/460)

6.5% (6/93)

14.0% (65/463)

36.6% (34/93)

25.9%* (120/463)

12.9% (9/70)

38.4%*** (178/463)

ASP

8-10

8.3%

(2/24)

79.2%***

(202/255)

0.0%

(0/41)

11.7%*

(30/257)

41.5%

(17/41)

21.4%**

(55/257)

20.0%

(7/35)

42.8%**

(110/257)

ASP

5-7

11.1%

(2/18)

86.4%***

(133/154)

10.3%

(3/29)

16.1%

(25/155)

41.4%

(12/29)

24.5%

(38/155)

7.4%

(2/27)

41.3%***

(64/155)

ASP

0-4

12.5%

(1/8)

80.4%***

(41/51)

14.3%

(2/14)

19.6%

(10/51)

28.6%

(4/14)

52.9%

(27/51)

0.0%

(0/8)

7.8%

(4/51)

*P-value<0.05 **P-value<0.01 ***P-value<0.001 for Penumbra treatment as compared to control using Fishers Exact Test

Outcome: 90-Day mRS 0-2 Control (N=70) and Penumbra System (N=463)

0.0% (0/8)

7.4% (2/27)

20.0% (7/35)

12.9% (9/70)

7.8% (4/51)

41.3% (64/155)***

42.8% (110/257)**

38.4%(178/463)***

0.0 10.0 20.0 30.0 40.0 50.0

Large (0-4)

Medium (5-7)

Small (8-10)

Overall

Penumbra

Control

90-Day Good Outcome %

ASP

EC

TS G

rou

p

*P-value<0.05

**P-value<0.01

***P-value<0.001 for Penumbra treatment as compared to control using Fishers Exact Test

Number of Patients Needed to Treat

(NNT) for Good Outcome

4 5

3

13

0

2

4

6

8

10

12

14

Overall Small (8-10) Medium (5-7) Large (0-4)

ASPECTS Group

Nu

mb

er

of

Pa

tie

nts

ASPECTS Group 95% CI

Small (8-10) 4.38 [2.68, 12.15]

Medium (5-7) 2.95 [2.15, 4.69]

Large (0-4) 12.8 [6.60, 227.3]

Discussion

Data confirms that endovascular therapy may

not be as successful in patients with large

infarct core

Leads to high NNT

Excluding this group may lower overall NNT and

improve response rate of this therapy

FIRST Trial: The Team

FIRST Trial: Texas Stroke Institute Physician Team

Chandril Chugh, MD Alex Venizelos, MD Keyur Patel, MD Suman Nalluri, MD

TSI Stroke & Neuro-critical Care Physicians

Parita Bhuva, MD Ryan Gianatasio, MD Paul A. Hansen, MD Vallabh Janardhan, MD

Director, TSI

TSI Stroke Intervention Physicians

Tanzila Shams, MD

TSI Research Fellow

Texas Stroke Institute Administrative Team

Kathy Sheets

VP, HCAPS

Will Smitham

VP, HCAPS

Operations

Josh Canfield

TSI Practice Manager

Mark Whitley

Sr. VP Bus. Dev.

Dana Davis

TSI Clinical

Coordinator

Helen Hare

Program Coordinator

Anita Guthmann

Director,

Comprehensive Stroke

Rubina Muzina, MD MPH,

Supervisor, Research

Office, Plaza Medical

Center of Fort Worth

Prof. Raymond Cheung

Rosalind Ge

Queen Mary Hospital

Prince Wales Hospital Dr. Thomas Leung

Roxanna Liu

Synapse Therapeutics (CRO)

Clinton Wong Irene Hung Karen Chan

Core Lab

Dr. Albert Yoo

Penumbra, Inc.

Siu Po Sit

Lynne Ammar

Denise Meyer

Leticia Barraza

Jessica Harpel

Susana S. Hak

Yosephine Lumintang

Sophia S. Kuo

Nam Nguyen

Hope Buell

Dawn Ueda

Q&A