Results of CRYSTAL AMI: A Pilot Trial Before INFUSE AMI, the Concept and Evolution in Thrombus Management

Saihari Sadanandan, MD, FACC, FASE, Dip. CBNC, FSCAIAssociate Professor of Clinical Medicine

Director, Vascular InterventionsDivision of Cardiology

IU- HealthIndiana University

Indianapolis

Disclosure - I

Speaker Bureau – Sanofi AventisBristol Myers SquibbDaichi Sankyo/Lilly

Educational Grant from Atrium Medicaltowards IRB fees to collect data on the case Studies

CRYSTAL – AMI slide courtesy – R. Dave, MD

Acute Inferior MI: Primary PCI for STEMI

Primary PCI for STEMI: Predilation and Stent

Distal Embolization during primary PCI for STEMI

5 year outcomes of No-reflow during Primary PCI for STEMI

• N = 1406

• Pts with STEMI undergoing PCI

• No reflow defined as TIMI <3 flow or TMPG 0-1 after successful PCI

• Occurred in 30% of pts

• 7-14 day infarct size 15% vs. 8% p<0.001

• 5-year mortality 18.2% vs. 9.5%, p < 0.001

Ndrepepa G, et al.. J Am Coll Cardiol. 2010;55:2383-2389.

Distal embolization and small distal vessel cutoff is neither infrequent norbenign!!!!

• Occurs in about 15% of patients undergoing PCI for STEMI

• Associated with larger infarct size, lower LVEF and increased long term Mortality

(Eur H J 2002:23-1112-17

(Eur H J 2002:23-1112-17

N=178No DE

n = 151 (85%)DE

n = 27 (15%)P Value

LVEF (%) 51 ± 9 42 ± 14 0.005

Cardiac enzyme

847 ± 631 1612 ± 1008 0.001

Mortality 15 (9%) 12 (44%) < 0.001

(Eur H J 2002:23-1112-17)

Distal embolization during Primary PCI for STEMI

IMPACT OF MYOCARDIAL BLUSH GRADE

0

2

4

6

8

Mo

rta

li ty

(%

) 6.2%

4.4%

2.0%

n=203 n=46 n=434

TMP Grade 3

P=0.05

n=79

5.1%

Normal ground-glassappearance of blush.Dye mildly persistent

at end of washout.

Dye strongly persistentat end of washout.

Gone by next injection.

Stain present.Blush persists

on next injection.

No or minimal blush.TMP Grade 2 TMP Grade 1 TMP Grade 0

Adapted from Gibson CM, et al. Circulation. 2000;101:125-130.

TIMI Myocardial Perfusion (TMP) Grades

80

85

90

953

2

0/1

100C

um

ula

tive

Su

rviv

al (

%)

0 2 4 6 8 10 1275

Final Blush Score (patients with final TIMI 3 flow)

Blush 1-Year Mortality32

0/1

6.8%13.2%18.3%

P=0.004

Myocardial Perfusion After Primary PCI is the Strongest Predictor of Mortality independently from IRA reopening

No reflow/ slow flow Poor TIMI flow

Poor MBG Larger Infarct size

Thrombus

Effects of Thrombo embolization during Primary PCI

2.7

5.3

3.1

4.4

2.83.4

0

2

4

6

Adjunctive device prior to PCI PCI alone

Meta-Analysis of Various Devices—Mortality

Bavry AA, Kumbhani D, Bhatt DL. Eur Heart J. 2008;29:2989-3001.

Mechanical thrombectomy

Catheter thrombus aspiration

Embolic protection

P = 0.018

P = 0.050

P = 0.69

Mo

rta

lity,

%

FZ 2008-12

TAPAS one year outcome: Myocardial blush grade and death

Death/reinfarction P= 0.001

Svilaas T et al. NEJM 2008;358-557 - FZ 2008-9 Myocardial blush grade

Burzotta et al. European Heart Journal (2009) 30, 2193-2203

Thrombectomy ± IIb/IIIa inhibitors

7.4%

5.0% 4.8%

3.3%

IIb/IIIa inhib -Thrombectomy -

IIb/IIIa inhib +Thrombectomy -

IIb/IIIa inhib –Thrombectomy

+

IIb/IIIa inhib +Thrombectomy

+

4%

2%

8%

6%

MORTALITY

P=0.02

Summary of Current Limitations in STEMI PCI

• No optimal method of thrombus management• Once embolization occurs in primary PCI , it is a

challenging scenario• Higher MACE, Infarct size with poor MBG• Aspiration catheters are good, but not uniformly

effective.• There may be a synergistic effect between

thrombectomy and GP-IIBIIIA receptor inhibitors

HOW CAN WE IMPROVE ON THIS FURTHER IN STEMI PCI?

COMBINE THE MECHANICAL APPROACH WITH PHARMACOLOGY -(INTRACORONARY DRUG)

MINIMIZE BLEEDING & MAXIMIZE DETHROMBOSIS

Meta Analysis of IC Versus IV Abciximab administration of peer reviewed studies (N=2,301) 997 STEMI, 1304 NSTEMI

Hansen et al. Journal of Invasive Cardiology Vol 22; 6. June 2010. 278-282.

Clearway Catheter and Intracoronary Abciximab

Localized Drug Delivery via ClearWay for Pharmacological Thrombectomy and Prevention of Distal Embolization

Occlusion

Containment

Infusion

During inflation, drug is being infused through the microporous balloon pores while blood flow is occluded, maximizing drug availability without substantial dilution by the systemic circulation.

Containment of the treatment zone provides extended residence time to help local drug bioavailability, concentration and dose

Controlled infusion at 1-4 ATM throughout the entire length of the targeted treatment zone provides increased residence time and uptake

IC vs. Clearway Abciximab: The Coctail Study

Tamburino, Capodanno, et al. J Cardiovasc Med 2009

Pre ReoPro through ClearWay

Post ReoPro through Clearway

Coctail study: Change in Thrombus score

37.9

4.25

0

5

10

15

20

25

30

35

40

ClearWay Inf. Guid. Cath. Inf.

P=0.002

N= 20 N =21

Tamburino, Capodanno, et al. J Cardiovasc Med 2009

Coctail study: Final TIMI MBG

2.78

2.56

2.45

2.5

2.55

2.6

2.65

2.7

2.75

2.8

ClearWay Inf. Guid. Cath. Inf.

ClearWay Inf.Guid. Cath. Inf.

P=0.24

N 20N 21Tamburino, Capodanno, et al. J Cardiovasc Med 2009

CRYSTAL AMI: Study DesignSingle center, prospectively randomized

IV Abciximab ClearWay™ IC Abciximab

R 1:1

PCI as per standard of care, EvaluateMBG, TIMI flow, ST Resolution, LV Function at Discharge

30 day follow up, Echo, Resting Sestamibi

STEMI within 6 hours, Heparin, 600mg Clopidogrel (n=50)

CRYSTAL- AMI: Demographics (N=48)

Treatment arm IC =25 IV=23

Male/Female M=23, F=2 M=18, F=5

Age 62 + 25 65 + 23

HTN 14 14

Angina 5 2

CHF 1 0

Prior PCI 6 2

CABG 3 1

DM 8 6

Lipids 14 9

Smoking C=9, F=2 C=6, F=0

Manual/Mechanical Extraction catheter use (discretion of operator)

16

12

2 2

7

9

0

2

4

6

8

10

12

14

16

18

IC IV

Manual

Angiojet

None

(n = 25) (n = 23)

TIMI Flow Comparison (N=48)

16

1

17

3 1

5

2

4

1

24

3

19

IC TIMI Pre IC TIMI Post IV TIMI Pre IV TIMI Post

3

2

1

0

82%

(n = 25) (n = 23)

TIMI Flow

96%

Primary Endpoint: TIMI Myocardial Blush Grade (MBG) >2 (N=48)

17

1

18

72

3

1

5

2

8

0

18

1

12

IC Blush Pre IC Blush Post IV Blush Pre IV Blush Post

3

2

1

0

92%86%

1

(n = 25) (n = 23)

MBG

92% of IC versus 86% of IV patients

MBG 3 and ST Resolution Rates comparison

18

12

21

18

IC Abciximab IV Abciximab

MBG 3

ST Resolution

• In Tapas, MBG 3 was only achieved in 45% of patients in extraction arm (identical to IV Abciximab group), but was directly linked to 5 times increase in mortality. IC Abciximab Administration through ClearWay™ has resulted in 72% of patients leaving the lab with a blush score of 3.

(n = 25) (n = 23)

72%

80%

52%

70%

Clinical Outcomes (N=48)

IC IVReadmissions 0 2

Death 0 1

Conclusions

• Our understanding of evaluation of surrogate markers which directly correlates to Mortality and Myocardial preservation has improved significantly

• Improving myocardial preservation also has profound economic impacts: low cost of care, better QOL, less need for ICD

• Localized superselective drug delivery (GP 2b3a inhibitors and vasodilators) with ClearWay as a stand alone device or when combined with Aspiration devices significantly improves MBG

• Series of data already promising, INFUSE AMI is underway…