Magnitude of Benefit of Endovascular Thrombectomy 6-24 ...wcm/@sop/@scon/documents/...Outcome mRS BPH NNT Dichotomized Asymptomatic 0 5 19 Freedom from Disability 0-1 23 4 Functional

Magnitude of Benefit of Endovascular Thrombectomy 6-24 Hours after Onset in Acute Ischemic Stroke Patients with Clinical-Core Mismatch

Saver Jl, Nogueira RG, Jadhav AP, Haussen DC, BonafeA, BudzikRF, Bhuva P, Yavagal DR, Ribo R, Cognard C, Haenl RA, Sila CA, Hassan AE, Liebeskind DS, Smith WS, Jovin TG, for the DAWN Investigators

Disclosures

• JLS, APJ, DCH, AB, RFB, PB, DRY, RR, CC, RA, CAS, AEH, DSL, WSS: consulting fees and

travel expenses for work advising on rigorous trial design and conduct

• RGN, TGJ: travel expenses only for work advising on rigorous trial design and conduct

Background: Patient Selection for Mechanical Thrombectomy

• Initial MT RCTs of highly effective devices generally

time-focused patient selection

• Pooled analysis - benefit rapidly decays, may be lost by 7.3 hours1

• National AHA+ESO guidelines endorsed only <6 hr window as IA

evidence2,3

• Physiologic, rather than purely time-based, selection

may identify patients >6 hr from LKW who benefit

• ~40% of AIS-LVO

• Wake-up onset

• Unclear onset time

• Witness late onset, slow progressorsunclear onset, wunclear onset time AIS-LVO

• Clinical-Core Mismatch - substantial deficits but limited infarct4

• DAWN tested this approach

1 Saver et al, JAMA. 2016 2 Powers et al, Stroke 2015 3 Wahlgren Int J Stroke 2016 et.al, 4 Jovin et.al, Stroke 2011

Outcomes = Collaterals

Time

Background: Indices of Treatment Benefit Magnitude

• DAWN

• Primary endpoint: Utility-Weighted modified Rankin Scale

• Group-level, average benefit directly interpretable

• Health-related utility, from 0% (death) to 100% (optimum health)

• Average patient xx% improvement


• DAWN





• Patient-level indices of benefit also would be helpful,

for patients, physicians, policy-makers

• Benefit per hundred (BPH): among 100 patients, how many benefit?

• Number needed to treat (NNT): How many need to be treated for 1 to

benefit?


• DAWN









benefit?

• Current study to derive BPH and NNT values

• Overall and in 6-12 and 12-24h time windows


• DAWN primary results: ESOC (5/17), NEJM (11/17)

• Primary endpoint: Utility-Weighted modified Rankin Scale, 5.5 vs 3.4

• Abs diff 2.0 (95CrI 1.1-3.0), post p > 0.999



• Average patient 20% improvement





benefit?

• Current study to derive BPH and NNT values

• Overall and in 6-12 and 12-24h time windows

Study design Global, multi-center, adaptive, population enrichment, prospective, randomized,

open, blinded endpoint (PROBE), controlled FDA IDE trial

Patient

population

• Acute ischemic stroke (AIS) with large vessel occlusion

• Able to be randomized between six to 24 hours after time last known well

• Clinical imaging mismatch (CIM) defined by age, core, and NIHSS

Target vessel Intracranial ICA, M1 segment of the MCA

Randomization 1:1 Trevo + medical management vs. medical management alone

Sites Up to 50 sites worldwide (30 US and 20 international)

Sample size 500 maximum subjects: 250 in the treatment arm and 250 in the control arm.

Minimum sample size is 150 subjects.

Follow-up 24 hours (-6/+24), day 5-7/discharge, day 30 (± 14), and day 90 (± 14)

Methods: DAWN DesignTo demonstrate superior functional outcomes at 90 days with Trevo plus medical

management compared to medical management alone in appropriately selected

patients treated six to 24 hours after last seen well

- Age 18

- NIHSS ≥10

- Pre-mRS 0-1

- TLSW to

Randomization:

6-24h

RAPID CTP/DWI CIM:

A. 80 y/o:

1. NIHSS 10 + core <21cc

B. <80 y/o:



1:1

Randomization:- CIM subgroup

- ICA-T vs M1

- 6-12 vs 12-24h

Control

Thrombectomy

90-day

mRS

Study Methods: Workflow

NCCT/DWI:

<1/3 MCA Territory

CTA/MRA:

ICA-T and/or MCA-M1(Tandem Occlusions Allowed)

Informed

Consent

- U-W mRS

- mRS 0-2

6-24h

TRIAL STOPPED FOR AT FIRST INTERIM EFFICACY ANALYSIS:

OVERWHELMING EFFICACY IN 1ST 200 PATIENTS

DAWN Trial Utility-Weighted mRS

Utility weighted mRS

• Better captures health state transitions across the entire spectrum

• Patient-centered outcomes analysis

Minimal Clinically Important Difference (MCID)

• MCID for health-related utility is well-established: 0.31

• 5 transitions on the mRS are clinically valuable

– 1 transition not clinically valuable, from mRS 6 to mRS 5

mRS 0 1 2 3 4 5 6

Weight 10 9.1 7.6 6.5 3.3 0 0

1 Kaplan et al, Health Serv Res 1976;11:478-507; Kaplan, COPD 2005;2:91-7 (0.3 value is scaled to 0-10 range of UW-mRSversion used in DAWN)

BPH and NNT Derivations

• Analyzed age, NIHSS, and core-adjusted 90d distributions

• For all dichotomized cutpoints of the mRS

• NNT and BPH values by calculating inverse of absolute risk difference

• For improvements on the UW-mRS (= improvements by 1 or

more levels across all steps of the 6 level mRS)

• NNT and BPH values by automated joint outcome table resampling

• R function “xsample” used to randomly sample values of the vector “x” from all possible joint

outcome table solutions

• Using the mirror algorithm, 3000 samples were taken from the large population of all possible

solutions, without replacement.

• Mean and range NNTB values were calculated for these random samples from all possible NNTB

values under the constraints

Endo

0 1 2 3 4 5+6

0 20 20

1 39 39

No Endo 2 19 19

3 208 208

4 317 317

5+6 397 397

20 39 19 208 317 397

Endo

0 1 2 3 4 5+6

0 40 40

1 11 40 51

No Endo 2 5 28 7 40

3 24 78 46 14 162

4 10 69 99 85 80 343

5+6 4 9 16 32 51 252 364

94 224 168 131 131 252

Endo

0 1 2 3 4 5+6

0 40 40

1 3 48 51

No Endo 2 4 6 30 40

3 22 63 35 42 162

4 17 85 85 64 92 343

5+6 8 22 18 25 39 252 364

94 224 168 131 131 252

Automated joint outcome table multiple resampling

Results

DAWN Treatment Group-Level Differences

Entire DAWN Cohort

mRS (6 level)Stacked Bar Chart


Entire DAWN Cohort

mRS (6 level)Stacked Bar Chart

UW-mRSUtility Staircase Plot

mRS Outcomes – Entire DAWN Cohort

Outcome mRS BPH

Dichotomized

Asymptomatic 0 5

Freedom from Disability 0-1 23

Functional Independence 0-2 36

Ambulatory 0-3 32

Not Requiring Constant Care 0-4 11


Outcome mRS BPH NNT

Dichotomized

Asymptomatic 0 5 19

Freedom from Disability 0-1 23 4

Functional Independence 0-2 36 3

Ambulatory 0-3 32 3

Not Requiring Constant Care 0-4 11 9


Outcome mRS BPH NNT

Dichotomized

Asymptomatic 0 5 19



Ambulatory 0-3 32 3



Outcome mRS BPH NNT

Dichotomized

Asymptomatic 0 5 19



Ambulatory 0-3 32 3


Entire Range

Lower Disability 0/1/2/3/4/5+6 50 2


Outcome mRS BPH NNT

Dichotomized

Asymptomatic 0 5 19



Ambulatory 0-3 32 3


Entire Range



Outcome mRS BPH NNT

Dichotomized

Asymptomatic 0 5 19



Ambulatory 0-3 32 3


Entire Range


For every 100 DAWN-like patients treated, thrombectomy yields improved

disability-related quality of life in 50, including functional independence in 36.


Time Window Cohorts

6-12 Hours

>12-24 Hours

mRS Outcomes – DAWN Time Window Cohorts

6-12 Hrs >12 – 24 Hrs

Outcome mRS BPH BPH

Dichotomized

Asymptomatic 0 7 3



Ambulatory 0-3 33 31



6-12 Hrs >12 – 24 Hrs

Outcome mRS BPH NNT BPH NNT

Dichotomized

Asymptomatic 0 7 14 3 33

Freedom from Disability 0-1 22 5 22 5

Functional Independence 0-2 33 3 36 3

Ambulatory 0-3 33 3 31 3

Not Requiring Constant Care 0-4 2 44 19 5


6-12 Hrs >12 – 24 Hrs

Outcome mRS BPH NNT BPH NNT

Dichotomized

Asymptomatic 0 7 14 3 33

Freedom from Disability 0-1 22 5 22 5

Functional Independence 0-2 33 3 36 3

Ambulatory 0-3 33 3 31 3

Not Requiring Constant Care 0-4 2 44 19 5

Entire Range

Lower Disability 0/1/2/3/4/5+6 45 2 56 2


Time Window Cohorts

6-12 Hours

>12-24 Hours


Time Window Cohorts

6-12 Hours

>12-24 Hours


Time Window Cohorts

6-12 Hours

>12-24 Hours

Discussion: Comparison with Other Thrombectomy Trials

DAWN

Disability-Related QoL(UW-mRS)

Level of Disability (mRS shift analysis)

Benefit Per Hundred*(Shift+Fxn Ind)

49 (36 /14)

*In comparative analyses, BPH values were calculated using the algorithmic min-max joint outcome table method (rather than the multiple resampling joint outcome table method)

Discussion: Comparison with Other Thrombectomy Trials – 1A

DAWN

HERMES 2H




49 (36 /14)

51 (32 /18)


Discussion: Comparison with Other Thrombectomy Trials – 1B




DAWN

HERMES 5H

49 (36 /14)

33 (14 /19)


Discussion: Comparison with Other Thrombectomy Trials - 2




49 (36 /14)

48 (29 /19)


Conclusions

• Endovascular thrombectomy with the Trevo device at 6-24h in patients with

clinical-core mismatch confers benefit of substantial magnitude, improving 90 day

disability levels in one-half of patients, including conferring functional

independence in one-third.

• Benefit is substantial in both the 6-12h and >12-24h time windows, with about half

of patients benefitting in both periods. But earlier patients do better in both the

thrombectomy and control groups.

• The proportion of patients benefitting in DAWN is similar in magnitude to that

observed in broadly screened patients selected for treatment at 2h, and

substantially higher than that seen for broadly selected patients at 5h.

Enrolling CentersNorth America

1. Abington Memorial, PA

2. Baptist Jacksonville, FL

3. Buffalo, NY

4. Capital Health Trenton, NJ

5. Christiana Delaware, DE

6. CPMC San Francisco, CA

7. Erlanger ,Chattanooga, TN

8. Florida Hospital, FL

9. Grady Atlanta, GA

10. JFK, Edison, NJ

11. Kaiser LA

12. Kennestone, Marietta GA

13. KUMC Kansas City, KA

14. Lexington Memorial, KY

15. Riverside, OH

16. Rush, IL

17. St. Joseph Mercy MI

18. Texas Stroke Institute TX

19. Toronto Western, ON

20. UCLA, CA

21. UH Cleveland, OH

22. University of Miami, FL

23. UPMC, PA

24. Valley Baptist, TX

Europe

26. Bellvitge Barcelona

27. Germans Trias Barcelona

28. Gui de Chauliac Montpellier

29. Hopital Purpan Toulouse

30. Hospital Clinic Barcelona

31. Vall d'Hebron Barcelona

Australia

32. Royal Melbourne Hospital

0

0

0

0

1

1

1

1

1

1

2

2

2

3

5

5

5

5

5

7

7

7

7

7

9

10

14

14

38

46

0 5 10 15 20 25 30 35 40 45 50 55 60

Lexington (PI: GIven, ATE 08/29/16) - 0 SPM

Kennestone (PI: Gupta, ATE 09/01/16) - 0 SPM

UCLA (PI: Starkman, ATE 11/21/16) - 0 SPM

Hospital Clinic (PI: Urra, ATE 02/22/17) - 0 SPM

JFK (PI: Kirmani, ATE 02/15/17) - 1.9 SPM

Capital (PI: Vez, ATE 07/01/14) - 0 SPM

Florida Hospital (PI: Hellinger, ATE 11/09/15) - 0.1…

Kaiser LA (PI: Feng, ATE 11/19/15) - 0.1 SPM

KUMC (PI: Abraham, ATE 02/01/16) - 0.1 SPM

Bellvitge (PI: Cardona, ATE 01/31/17) - 1 SPM

Erlanger (PI: Devlin, ATE 06/05/15) - 0.1 SPM

Memorial Regional (PI: Mehta, ATE 02/26/16) - 0.2…

Toronto Western (PI: Silver, ATE 08/26/16) - 0.3 SPM

Abington (PI: Shah, ATE 10/29/15) - 0.2 SPM

CPMC (PI: English/Barazangi, ATE 05/05/15) - 0.2…

Rush (PI: Chen, ATE 05/07/15) - 0.2 SPM

Royal Melbourne (PI: Mitchell, ATE 11/12/15) - 0.3…

Buffalo (PI: Levy, ATE 12/01/15) - 0.3 SPM

Germans Trias I Pujol Badalona (PI: Millán Torné ,…

Valley Baptist (PI: Hassan, ATE 03/31/15) - 0.3 SPM

UH Cleveland (PI: Sila, ATE 05/04/15) - 0.3 SPM

Baptist Jacksonville (PI: Hanel, ATE 01/21/16) - 0.5…

Hopital Purpan Toulouse (PI: Cognard, ATE…

Vall d'Hebron Barcelona (PI: Ribo, ATE 05/19/16) -…

University of Miami (PI: Yavagal, ATE 09/01/16) -…

Texas Stroke Institute (PI: Bhuva, ATE 04/10/15) -…

Gui de Chauliac Montpellier (PI: Bonafe, ATE…

Riverside (PI: Budzik, ATE 08/28/14) - 0.5 SPM

Grady (PI: Nogueira/Hassen, ATE 11/25/14) - 1.4 SPM

UPMC (PI: Jadhav, ATE 10/31/14) - 1.6 SPM

SPECIAL ACKNOWLEDGEMENTS STRYKER NEUROVASCULAR DAWN CLINICAL TEAM

• Alice Lin, CRA, Lead Clinical Research Associate

• Patricia Morgan, BSN, RN, Lead Clinical Research Associate

• Ryan Shields, MSc, Sr. Manager, Data Management and Biostatistics

• Christine Toruno MSc, DAWN Project Manager

Thank youto all DAWN investigators, patients and families

Documents

Magnitude of Benefit of Endovascular Thrombectomy 6-24 ...wcm/@sop/@scon/documents/...Outcome mRS BPH NNT Dichotomized Asymptomatic 0 5 19 Freedom from Disability 0-1 23 4 Functional