Post on 17-Dec-2015
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
COBRA TrialCOBRA Trial Cryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For
Revascularization of Peripheral Arterial Segments
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
Revascularization of Peripheral Arterial Segments
• 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*
COBRA TrialCOBRA Trial
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
COBRA TrialCOBRA Trial
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
COBRA TrialCOBRA Trial
Cryoplasty n = 45
Conventional balloon
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
COBRA TrialCOBRA Trial
Cryoplasty n = 45
Conventional balloon
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
COBRA TrialCOBRA Trial
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.)
COBRA TrialCOBRA Trial
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
COBRA TrialCOBRA Trial
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
COBRA TrialCOBRA Trial
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
COBRA TrialCOBRA Trial
SFA Chronic total occlusion12m binary restenosis
70.0%70.0%
36.0%36.0%
ConventionalBalloon Post-dilation
n=20
CryoplastyBalloon Post-dilation
n=25
30%
90%
60%p=0.06
COBRA TrialCOBRA Trial
*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*
COBRA TrialCOBRA Trial
Bilateral SFA nSES Implants12m binary restenosis
66.7%66.7%
26.7%26.7%
ConventionalBalloon Post-dilation
n=15
CryoplastyBalloon Post-dilation
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
Revascularization of Peripheral Arterial Segments
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
COBRA TrialCOBRA Trial Cryoplasty or Conventional Balloon Post-dilation of Nitinol Stents For
Revascularization of Peripheral Arterial Segments
• 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