mistral-c: a prospective randomized trial of embolic protection

MISTRAL-CMRI Investigation in TAVI with Claret

N.M. Van Mieghem, MD, PhD; L. van Gils, MD; H. Ahmad, MD; F. van Kesteren, MD; H.W. van der Werf, MD; A.F.M. van den Heuvel, MD, PhD; G. Brueren, MD, PhD; A. van den

Heuvel, MD, PhD; P. Tonino, MD, PhD; J. Baan, MD, PhD; M. Schipper, MD, PhD; A. van der Lugt, MD, PhD; P. P.T. de Jaegere, MD, PhD

Dutch trial register-ID: NTR4236

Disclosure Statement of Financial Interest

• Grant/Research Support

• Consulting Fees/Honoraria• Major Stock Shareholder/Equity

• Medtronic, Edwards Lifesciences; St Jude, Claret Medical

• Abbott VAscular• Claret Medical

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

Van Mieghem N. et al. Circulation 2013;127:2194-201 Walters et al. Circulation 2014;129:504-515

*

**

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D

A CB

E

F G

8mm

Background – Cerebral Embolization with TAVI

Dual (proximal and distal)

independent filter embolic

protection device

3rd generation

Deflectable compounded curve

sheath to facilitate cannulation of

LCC

Claret Sentinel™ Cerebral Protection System

MISTRAL-C

• Aim: does Sentinel EPD affect new brain lesions &

neurocognitive performance after TAVI

• Design: multi-center double-blind randomized trial enrolling

patients with symptomatic severe aortic stenosis and 1:1

randomization to TAVI with or without Sentinel EPD

• Power Calculation: n= 54 to demonstrate a reduction of

new brain lesions by DW-MRI from 80% to 40% with the

Sentinel EPD and based on the continuity corrected chi-

square test (80% power and a 2-sided alpha of 0.05).

MISTRAL-C – Study Investigations

3-Tesla brain MRI study assessed by 2 experienced study-

blinded neuro-radiologists

Neurologic & neurocognitive testing by trained study-

blinded neurology specialists

CES-D

Mini-Mental State Examination(MMSE)

Montreal Cognitive Assessment (MOCA)

Pathology study of all retrieved filters by experienced

pathologist

Clinical outcome according to VARC-2

TAVI ProcedureDay 0

TAVI – 1 Day

Consent for TAVI & MISTRAL-C study

3T Neuro-MRi

Neurocognitive testing

Clinical neurological exam

TAVI + 5 Days

3T Neuro-MRi

Neurocognitive testing

Clinical neurological exam

Randomization Sentinel vs. Control

Transcranial Doppler

Pathology

MISTRAL-C

From January 2013 – August 2015 65 patients were enrolled

Day

TAVI -1

Day

TAVI

Day

TAVI + 5

Day

TAVI + 30

Any new

neurological

event

6 months

Brain MRi X X

X

X

Neurological

assessment

X

X

X

Neurocognitive

function

X

X

X

MSCT scan X* X**

Clinical status X X X X X X

* Within 3 months prior to TAVI; ** Neuro-imaging(MSCT or MRi is encouraged and per neurologist's decision

Investigation Timeline

Baseline Characteristics

Sentinel (n=32) No Sentinel (n=33) Total (N=65) P-value

Age 81 (79-84) 82 (77-86) 81 (78-85) 0,604

Female 15 (47%) 16 (49%) 31 (48%) 0,897

Hospital

Erasmus Medical Center Rotterdam 28 (88%) 30 (91%) 58 (89%)

Amsterdam Medical Center 2 (6%) 1 (3%) 3 (5%)

University Medical Center Groningen 1 (3%) 1 (3%) 2 (3%)

Catharina Ziekenhuis Eindhoven 1 (3%) 1 (3%) 2 (3%)

Hypertension 21 (66%) 23 (70%) 44 (68%) 0,726

Diabetes 4 (13%) 9 (27%) 13 (20%) 0,137

Previous Myocardial Infarction 2 (6%) 2 (6%) 4 (6%) 0,975

Peripheral arterial disease 9 (28%) 11 (33%) 20 (31%) 0,649

Previous TIA/CVA 6 (19%) 6 (18%) 12 (19%) 0,953

Procedural Characteristics

Claret (n=32) No Claret (n=33) Total (N=65) P-value

Constrast volume in ml (median, IQR) 126 (100-148) 113 (71-176) 120 (88-158) 0,581

ACT at time of implant in seconds (median, IQR) 202 (164-251) 190 (162-213) 194(163-237) 0,149

Number of balloon inflations (n,%)

0,853

0 1 (3%) 1 (3%) 2 (3%)

1 16 (50%) 17 (52%) 33 (51%)

2 13 (41%) 13 (39%) 26 (40%)

≥3 2 (6%) 2 (6%) 4 (6%)

Number of valves implanted (n,%)

0,5910 1 (3%) 2 (6%) 3 (5%)

1 31 (97%) 30 (91%) 61 (94%)

≥2 0 (0%) 1 (3%) 1 (2%)

Sentinel device successfully deployed (n,%) 30 (94%) N/A N/A

Edwards Sapien 3

54%

Medtronic CoreValve

25%

Edwards SapienXT 15%

Balloon Dilatation

5%

Portico1%

Clinical outcome @ 30 Days

Sentinel (n=32) No Sentinel (n=33) P-value

Mortality (n,%)

≤ 5 days 1 (3%) 0 (0%) 0,313

≤ 30 days 1 (3%) 3 (10%) 0,334

≤ 6 months 1 (5%) 4 (17%) 0,187

Major stroke ≤ 30 days (n,%) 0 (0%) 2 (7%)* 0,144

* All strokes were fatal

Brain MRI n=37

Lesions @ baseline MRI: 11%

Median number of days to MRI: 5 (IQR 5-5)

No FU MRI: 43%

37 of powered 54 MRIs

Pacemaker36%

Patient refused21%

Dead / Unstable

18%

Other14%

Delirium11%

Reason for MRI dropout N=28

Dropout in other studies

DEFLECT-I 24%

DEFLECT-II 21%

DEFLECT-III 41%

PROTAVI-C 33%

CLEAN TAVI @D2 7%

CLEAN TAVI @D30 22%

Perspective

0

76

0

100

200

300

400

500

600

Sentinel (n=22) No Sentinel (n=15)

Le

sio

n v

olu

me

in

mm

3

Anterior

Total Lesion Volume

95

197

0

100

200

300

400

500

600


Le

sio

n v

olu

me

in

mm

3

Overall

P=0,171

P=0,057

56 76

0

100

200

300

400

500

600


Le

sio

n v

olu

me

in

mm

3

Posterior

P=0,571

Perspective

EPD+ EPD-

DEFLECT-I 20 N/A

DEFLECT-II 96 129

DEFLECT-III46% >150 mm3

48% >150 mm3

PROTAVI-C 305 180

Samim et al. 112 129

CLEAN-TAVI 220/471* 472/800*

* MRI was performed at 2 & 7 days

Total lesion volume per valve type

79

174

0

100

200

300

400

500

600


Le

sio

n v

olu

me

in

mm

3

BEV

19

214

0

100

200

300

400

500

600


Le

sio

n v

olu

me

in

mm

3

SEV

P=0,175 P=0,439

1 10

2

4

6

8

10

12

14

16


Nu

mb

er

of

lesio

ns (

me

dia

n)

Posterior

01

0

2

4

6

8

10

12

14

16


Nu

mb

er

of

lesio

ns (

me

dia

n)

Anterior

2 2

0

2

4

6

8

10

12

14

16


Nu

mb

er

o l

esio

ns

Overall

Number of Lesions

P=0,274

P=0,065 P=0,586

Perspective

EPD+ EPD-

DEFLECT-I 3 N/A

DEFLECT-II 6 5

DEFLECT-III N/A N/A

PROTAVI-C 8 4

Samim et al. 9 5

CLEAN-TAVI 8 / 5* 4 / 3*

* MRI was performed at 2 & 7 days

Number of lesions

2 2

0

2

4

6

8

10

12

14

16


Nu

mb

er

o l

esio

ns

BEV

4

8

0

2

4

6

8

10

12

Sentinel (n=6) No Sentinel (n=3)N

um

be

r o

le

sio

ns

SEV

P=0,346 P=0,435

Single Lesion Volume

55 54

0

50

100

150

200


Le

sio

n v

olu

me

(m

m3

)

Anterior

57

82

0

50

100

150

200


Le

sio

n v

olu

me

(m

m3

)

Posterior

5475

0

50

100

150

200


Le

sio

n v

olu

me

(m

m3

)

Overall

P=0,717 P=0,488

P=0,313

Perspective

EPD+ EPD-

DEFLECT-I 30 N/A

DEFLECT-II 14 25

DEFLECT-III 31 35

PROTAVI-C 30 50

Samim et al. 15 25

Single lesion volume per Valve type

48

65

0

50

100

150

200

250


Le

sio

n v

olu

me

(m

m3

)

BEV

5574

0

50

100

150

200

250

300

Sentinel (n=6) No Sentinel (n=3)Le

sio

n v

olu

me

(m

m3

)

SEV

P=0,324 P=0,881

Patients with no lesions

50%

20%

0%

50%

100%

Sentinel (n=22) No Sentinel (n=15)Pro

po

rtio

no

f p

ati

en

ts(%

)

Anterior

p=0,065

36% 33%

0%

50%

100%


Pro

po

rtio

no

f p

ati

en

ts(%

)

Posterior

p=0,850

27%

13%

0%

50%

100%


Pro

po

rtio

no

f p

ati

en

ts(%

)

Overall

p=0,312

Perspective

EPD+ EPD-

DEFLECT-I 18 N/A

DEFLECT-II 9 5

DEFLECT-III 21 12

PROTAVI-C 0 0

Samim et al. 0 5

Impact of THV

79

174

0

100

200

300

400

500

600


Le

sio

n v

olu

me

in

mm

3

BEV

19214

0

100

200

300

400

500

600


Le

sio

n v

olu

me

in

mm

3

SEV

P=0,175 P=0,439

Total Lesion Volume

2 20

5

10

15

20

Sentinel (n=16) No Sentinel (n=12)Nu

mb

er

o l

esio

ns

BEV

4

8

0

5

10

15


mb

er

o l

esio

ns

SEV

P=0,346 P=0,435

Number of Lesions

Patients with no lesions per valve type

31%

17%

0%

50%

100%


Pro

po

rtio

no

f p

ati

en

ts(%

)

BEV

p=0,378

17%

0%0%

50%

100%


Pro

po

rtio

no

f p

ati

en

ts(%

)

SEV

p=0,453

Neurocognitive assessments – ITT n=50

27.36 27.61

26.50

25.73

Baseline Day 5

MMSE

Sentinel No Sentinel

22.25

23.21

21.53 21.21

Baseline Day 5

MoCA


10.69

9.27

11.60 10.80

Baseline Day 5

CES-D


0.65 0.54

0.32

1.45

Baseline Day 5

NIHSS


p=0,718

p=0,086 p=0,172

p=0,201

Neurocognitive assessments – ITT

Score Sentinel (N=28) No Sentinel (N=22) P-value comparison Sentinel / No sentinel

RemarkBaseline SD Day 5 SD Difference P-value Baseline SD Day 5 SD Difference P-value

MMSE 27,36 3,29 27,61 2,36 0,25 0,409 26,50 2,44 25,73 3,72 -0,77 0,166 0,086(More is better)

MoCA 22,25 4,52 23,21 4,17 0,96 0,111 21,53 4,49 21,21 5,48 -0,32 0,669 0,172(More is better)

CES-D 10,69 6,75 9,27 5,28 -1,04 0,124 11,60 9,55 10,80 9,99 -0,80 0,545 0,718(Less is better)

NIHSS 0,65 1,65 0,54 1,53 -0,12 0,265 0,32 1,29 1,45 6,17 1,14 0,288 0,201(Less is better)

Deterioration in neurocognitive status – ITT

4%

13%8%

0%

27% 26% 25%

5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

MMSE worsening MoCA worsening CES-D worsening NIHSS worsening

Pro

po

rtio

n o

f p

atie

nts

(%

)

Claret (n=28) No Claret (22)

p=0,017 p=0,248 p=0,105 p=0,272

Neurocognitive assessments – AT (n=48)

27.36 27.61

26.80

25.95

Baseline Day 5

MMSE


22.25

23.21

21.67 21.33

Baseline Day 5

MoCA


10.69

9.27

11.68 10.89

Baseline Day 5

CES-D


0.65 0.54

0.33

1.52

Baseline Day 5

NIHSS


p=0,178

p=0,192p=0,720

p=0,072

Score Sentinel (N=28) No Sentinel (N=20) P-value comparison Sentinel / No sentinel

RemarkBaseline SD Day 5 SD Difference P-value Baseline SD Day 5 SD Difference P-value

MMSE 27,36 3,29 27,61 2,36 0,25 0,409 26,80 2,31 25,95 3,83 -0,85 0,154 0,072 (More is better)

MoCA 22,25 4,52 23,21 4,17 0,96 0,111 21,67 4,58 21,33 5,62 -0,33 0,669 0,178 (More is better)

CES-D 10,69 6,75 9,27 5,28 -1,04 0,124 11,68 9,80 10,89 10,25 -0,79 0,571 0,720 (Less is better)

NIHSS 0,65 1,65 0,54 1,53 -0,12 0,265 0,33 1,32 1,52 6,31 1,19 0,289 0,192 (Less is better)

Neurocognitive assessments – AT

Deterioration in neurocognitive status – AT

4%

13%8%

0%

30% 28% 26%

5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

MMSE worsening MoCA worsening CES-D worsening NIHSS worsening

Pro

po

rtio

n o

f p

atie

nts

(%

)

Sentinel (n=28) No Sentinel (20)

p=0,011 p=0,212 p=0,089 p=0,261

Transcranial Doppler (n=20)

956

684

0

500

1000

1500

2000


mb

er

of

HIT

S p

er

pa

tie

nt

HITS total

799633

0

500

1000

1500

2000


mb

er

of

HIT

S p

er

pa

tie

nt

HITS gaseous

54 58

0

50

100

150

200


Nu

mb

er

of

HIT

S p

er

pa

tie

nt

HITS solid

P=0,552

P=0,501 P=0,843

Historical data

Total Gasseoous Solid

EPD+

DEFLECT-I836 650 186

EPD-

Kahlert et al. 473 N/A N/A

Erdoes et al. 548 N/A N/A

Histopathology of Retrieved Filters (n=31)

Limitations

In Conclusion

Systematic brain MRI follow up in elderly patients undergoing TAVI is challenging

Sentinel EPD captures and retrieves debris en route to the brain in ± all TAVI patients

Elderly patients undergoing TAVI with Sentinel EPD have @ 5 days trends towards fewer new brain lesions & smaller total lesion volume

especially in the anterior and middle lobes.

less chance of neurocognitive deterioration

Adequately powered trials should confirm these findings

mistral-c: a prospective randomized trial of embolic protection

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