COBRA Trial COBRA Trial Cryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For...

COBRA TrialCOBRA Trial Cryoplasty or Conventional Balloon

Post-dilation of Nitinol Stents For Revascularization of

Peripheral Arterial Segments

Subhash Banerjee, MDChief, Division of Cardiology, VA North Texas Health Care

Associate Prof. of Medicine,

UT Southwestern Medical Center

Dallas, TX

On behalf of COBRA investigators:

ClinicalTrial.gov Identifier: NCT00827853

Disclosure Statement of Financial Interest

• Grant/Research Support

• Consulting Fees/Honoraria

• Major Stock Shareholder/Equity• Ownership/Founder• Intellectual Property Rights

• Boston Scientific Corporation, Medicines Company, Gilead, Relypsa

• Medtronic, Cordis, St Jude, Gilead, Boehinger, Sanofi

• Mdcare Global (spouse)• Mdcare Global (spouse)• Mdcare Global (spouse)

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

Affiliation/Financial Relationship Company

COBRA TrialCOBRA Trial Cryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For

Revascularization of Peripheral Arterial Segments

• Investigators: Subhash Banerjee, MD VA North Texas HCS/UTSW

Emmanouil S. Brilakis, MD, PhD VA North Texas HCS/UTSW

Tony Das, MD Presbyterian Hospital of Dallas

Kenneth Saland, MD Presbyterian Hospital of Dallas

Mazen Abu-Fadel, MD Oklahoma City VAMC/OU

Faisal Latif, MD Oklahoma City VAMC/OU

Eric Dipple, MD Midwest CV Research Foundation

Nicholas Shammas, MD Midwest CV Research Foundation

*UTSW: University of Texas Southwestern Medical Center±VAMC: VA Medical Center¥ OU: Oklahoma University



Cryoplasty• PolarCath® peripheral dilatation system simultaneously dilates & cools the vessel wall

• Cooling (-10oC) is achieved by inflating the balloon with nitrous oxide instead of saline and contrast

PolarCath is a trademark of Boston Scientific Corporation and its affiliates.Image property of Boston Scientific Corporation

1Isner et al, Circulation; 1995 2Virmani et al, CryoLetters; 2005

Mechanisms of Action Induces smooth muscle cell (SMC) apoptosis1

Minimizes SMC necrosis (-5 to -15oC)2

Reduces in-stent restenosis (ISR)

N2O Refrigerant

Cylinder

Microprocessor-Controlled

Inflation Unit

Balloon

Catheter

COBRA TrialCOBRA TrialCryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For


• Background: Diabetes mellitus is associated with increased risk of in-stent restenosis after superficial femoral artery (SFA) stenting with nitinol self-expanding stents (nSES)1

• Hypothesis: When compared to conventional balloon angioplasty, cryoplasty post-dilation decreases the risk of SFA nSES in-stent restenosis

1Bakken et al, Journal of Vasc Surgery; 2007

COBRA TrialCOBRA Trial

Design

• DESIGN: Prospective, randomized, multi-center clinical evaluation of the PolarCath® system vs. conventional balloon post-dilation of nSES implanted in the SFA of patients with DM, presenting with life-style limiting claudication

• OBJECTIVE: To compare the rates of binary restenosis, at 12 months, as determined by duplex ultrasound (DUS)

121 patients with DM consented between August 2008 and December 2010 in 4

clinical sites in U.S.

47 (39%) patients not stented

nSES: nitinol self-expanding stents *Excluded from stent based primary analysis

≥2.5 times increase in Doppler peaksystolic velocity (PSV) in the stented

segment and 10mm beyond itsproximal and distal edges

90 SFA nSES implanted(74 patients/16 B/L)

Cryoplasty Group(N=45)

Conventional Balloon Group or CBA (N=45)

nSES Post-dilationRandomization 1:1

DUS and clinical follow-up at 12

months in 91.1% (N=41)

DUS and clinical follow-up at 12

months in 95.5% (N=43)

4 (8.9%) Deaths*

2 (4.4%) Deaths*


Inclusion Criteria

1. Diabetics, insulin or non-insulin dependent above 21 years of age

2. Severe intermittent claudication (RB stage 3), chronic critical limb ischemia with rest pain (RB stage 4), or chronic critical limb ischemia with ischemic ulcers (RB stage 5)

3. SFA nSES length ≥ 60 mm

4. SFA nSES diameter ≥ 5 mm

1Banerjee et al, Am J of Cardiology; 2009

Exclusion Criteria

1. Serum creatinine ≥ 2.0 mg/dl

2. Absence of at least 1 vessel brisk infra-popliteal run-off to the foot

3. LV ejection fraction ≤ 25%

4. Allergy to iodinated contrast

5. Allergy to aspirin or clopidogrel

6. Relative or absolute contraindication to anticoagulation

7. WBC < 3,000K/UL; platelet count < 100,000K/UL; Hgb < 10 g/dl

Sample size calculation: assuming 65% and 35% restenosiswith conventional balloon and cryoplasty treatments and 10% attrition, for an alpha =

0.05 and power =80%, 43 vascular segments would be needed in each treatment arm1


Cryoplasty n = 45

Conventional balloon

n = 45p Value

Age (years ± SD) 62.93 ± 12.97 64.87 ± 9.61 0.42

Male 82% 93% 0.11

Hypertension 98% 96% 0.16

Hyperlipidemia 96% 93% 0.32

Diabetes mellitus 100% 100% 1.00

Tobacco use 56% 60% 0.76

Chronic kidney disease

9% 13% 0.59

Coronary artery disease

67% 64% 0.70

Prior MI 24% 18% 0.44

Baseline Characteristics

MI: myocardial infarction


Cryoplasty n = 45


n = 45p Value

Hemoglobin A1C 7.43 ± 1.77 7.63 ± 2.16 0.67

Insulin requiring DM 16% 22% 0.39

Serum creatinine 1.14 ± 0.33 1.11 ± 0.29 0.60

Aspirin 69% 60% 0.38

Clopidogrel 40% 53% 0.21

Warfarin 13% 4% 0.14

Statin 89% 76% 0.10

ACEI/ARB 80% 69% 0.23

Beta blocker 62% 71% 0.38

Proton pump inhibitor 24% 20% 0.66

Baseline Characteristics

ACEI: angiotensin converting enzyme inhibitor ARB: angiotensin receptor blocker


Cryoplasty n = 45


n = 45p Value

Mean Rutherford stage 3.18 3.14 0.66

Baseline ABI 0.59 ± 0.21 0.62 ± 0.19 0.50

Lesion length (mm) 146.85 ± 97.03 149.35 ± 100.00 0.90

No. of run-off vessels 2.1 ± 0.9 2.0 ± 0.9 0.60

Chronic total occlusions 56% 44% 0.06

Total stent length (mm) 183.62 ± 123.10 197.35 ± 109.79 0.58

Stent diameter (mm) 6.09 ± 0.55 6.10 ± 0.30 0.87

Debulking 36% 27% 0.45

Post-dilations Balloon length (mm) 83.53 ± 28.69 86.18 ± 44.16 0.72

Balloon diameter (mm) 5.23 ± 0.51 5.51 ± 0.72 0.02

Number of dilations 2.51 ± 1.65 2.17 ± 1.01 0.25

Procedural Characteristics

ABI: ankle-brachial index


PolarCath® Post-dilation of nSES

ACT: activated clotting time UFH: unfractionated heparin

Mid SFA CTO 2v run-off CTO crossing Confirmation Polarcath® postdil Final result

Procedural success 100%Mean fluoroscopy time 31.82 ± 20.30 minMean ACT 238.21 ± 32.31UFH 79%Procedural adverse events 8.9% (Cryo.) 6.7% (Conv.)


Primary endpoint: 12m binary restenosis

55.8%55.8%

29.3%29.3%

ConventionalBalloon Post-dilation

n=43

CryoplastyBalloon Post-dilation

n=41

20%

60%

40%

p=0.01


ACT: activated clotting time UFH: unfractionated heparin

Cumulative hazard of restenosis

Cryoplasty 45 45 45 43 39 35 33Conventional 45 44 42 36 32 29 21

Time (in days)

Cu

mu

lati

ve h

azar

d o

f re

sten

osi

s HR=2.39, 95% CI 1.19 – 4.78p<0.01HR=2.39, 95% CI 1.19 – 4.78p<0.01

ConventionalCryoplastyConventionalCryoplasty


Change in ABI from baseline at 12m

Conventional BalloonPost-dilation

Baseline 12mCryoplasty Balloon

Post-dilation

Baseline 12m

p=0.66

ABI: ankle-brachial index

COBRA TrialCOBRA TrialChange in WIQ* from baseline at 12m

Conventional BalloonPost-dilation

Cryoplasty BalloonPost-dilation

Baseline 12m Baseline 12m

p=0.002

p=0.005

*Walking impairment questionnaire score


SFA Chronic total occlusion12m binary restenosis

70.0%70.0%

36.0%36.0%


n=20


n=25

30%

90%

60%p=0.06


*Compared to reference group

Cumulative hazard of restenosis (Non-CTO vs. CTO)C

um

ula

tive

haz

ard

of

rest

eno

sis

Time (in days)

Reference GroupReference Group

HR=2.65, 95% CI 0.72 – 9.80; p=0.15*HR=2.65, 95% CI 0.72 – 9.80; p=0.15*

HR=2.69, 95% CI 0.74 – 9.85; p=0.13*HR=2.69, 95% CI 0.74 – 9.85; p=0.13*

HR=3.61, 95% CI 0.99 –13.18; p= 0.05*HR=3.61, 95% CI 0.99 –13.18; p= 0.05*


Bilateral SFA nSES Implants12m binary restenosis

66.7%66.7%

26.7%26.7%


n=15


n=15

30%

90%

60%p=0.03

Analysis excludes 1 patient with same treatment to B/L LE

COBRA TrialCOBRA TrialCryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For


Conclusions

• In patients with diabetes mellitus presenting with life-style limiting claudication, post-dilation of nitinol self-expanding stents in the SFA using PolarCath®

cryoplasty significantly reduced 12-month in-stent restenosis compared to conventional balloon post-dilation

• These results indicate the potential impact of stent post-dilation strategies on endovascular treatment of symptomatic peripheral arterial disease



• Acknowledgements: Tayo Addo, MD DSMB chair Bertis Little, PhD DSMB member Kevin Kelly, PharmD DSMB member Rick Weideman, PharmD DSMB member Ravi Sarode, MD DSMB member Christopher Lichtenwalter, MD Core laboratory analysis Lorenza Makke, RVT Core laboratory analysis

Preeti Kamath, BDS, MHA Lead study coordinator

Daniel Tran, MSc Data manager Boston Scientific Corporation Research grant support Dallas VA Research Corp. Research administration

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