Transcript Treatment of Thrombotic Lesions

Treatment of
Thrombotic Lesions
Ramesh Daggubati, MD FACC FSCAI
Director of Interventional Cardiology
East Carolina University
Greenville, NC USA
AMI: Pathophysiology
Ruptured plaque with occlusive
thrombus
Geoffrey Hartzler, M.D.
First Primary Angioplasty in AMI, 1979
1946 - 2012
CADILLAC (n=2,082): 12 Month MACE
25%
PTCA, no abciximab
Stent, no abciximab
PTCA, abciximab
Stent, abciximab
22.4%
20.6%
20%
15%
14.5%
13.3%
10%
P<0.000001
5%
0%
0
2
4
6
8
Months to event
Stone GW et al. NEJM 2002;346:957-66
10
12
Acute
• Slow flow , No reflow
• Increased infarct size
30 day
• Early stent thrombosis
• Increased mortality
Long
term
• Delayed stent mal-apposition
• Late / very late stent thrombosis
THROMBUS MANAGEMENT IN AMI
HOW ?
APPROACHES
Pharmacologica
l
ASPIRATION
Thrombolysis
Export
Embolic
Protection
Distal
Protection
On site
protection
M Guard
Bivalirudin
Proximal
Protection
GpIIbIIIa
inhibitors
Thrombectom
y
antiplatelets
Combination
Self
Expanding
stent
MECHANICAL APPROACHES
ASPIRATION
Export
Thrombectomy
MECHANICAL APPROACHES
Embolic Protection
Distal Protection
Proximal Protection
Combination
Thrombectomy
Thrombus aspiration
Embolic Protection
TAPAS Trial-Results
Primary end point: TIMI flow1
Secondary endpoint (1 y)2
60
P < 0.001
Patients (%)
50
40
46
41
0/1
2
3
37
32
30
20
26
17
Death or Reinfarction (%)
12
10
Conventional PCI
Thrombus-Aspiration
10
Log rank
p=0.016
8
6
4
2
0
0
0
200
300
400
Time (days)
12
Conventional PCI
statistically significant
• MBG
• lower mortality at 1y
• Death/MI rate at 1 year FU
N= 1071 STEMI pts
90 % Abciximab usage
Conventional PCI
Thrombus-Aspiration
10
Mortality (%)
Thrombus
aspiration
100
8
Log rank
p=0.040
6
4
2
0
0
100
200
Time (days)
1. Svilaas et al, TAPAS 30days results, NEJM 2008;358,p.557.
2. Vlaar et al., TAPAS 1 year results, Lancet 2008;371,9628,p.1915
300
400


Myocardial blush grade predicts clinical
outcome at 1 year
Thrombus aspiration results in a lower
mortality and combined mortality and nonfatal reinfarction at 1 year
FZ 2008-15
Potential additive benefits of
Thrombus aspiration combined
With pharmacological support by
GPIIbIIIA -
Burzotta et al, EHJ 2009; 30: 2193-2203
Can we conclude “ proof of
principle”?
Not at all !!!
Does thrombectomy improve :
*ST segment resolution
*TIMI 3 flow
*corrected TIMI frame count
* myocardial blush
Some studies show benefit, not all
Limit infarct size?
No
Improve clinical outcomes?
Only in TAPAS
In hospital AIMI death increased

ESC 2010 myocardial revascularization guidelines:
“Manual catheter thrombus aspiration should be
considered during PCI of the culprit lesion in
STEMI”.

ACC/AHA 2009 focused update: “Aspiration
thrombectomy is reasonable for patients undergoing
primary PCI .
Based on the 2009 Focused Update of the ACC/AHA Guidelines for Management of Patients With STEMI
(Circulation and JACC 2009), and the ESC guidelines for myocardial revascularization (Eur Heart J 2010)
UCR
Uppsala Clinical
Research Center
Results and Methodology of a Registry based
Randomized Clinical Trial (RRCT)
Ole Fröbert, MD, PhD - on behalf of the TASTE investigators
Departement of Cardiology
Örebro University Hospital
Sweden
/ Swedish registry data
PCI alone (N=16 417)
TA+PCI (N=3 666)
HR (95% CI): 1.21 (1.08-1.35)
Vlaar, P.J. et al. The Lancet 2008; 371:1915
Fröbert, O. et al. Int J Cardiol. 2010; 145:572
TASTE
Enrolled in Denmark
N=247
trial enrollment flow chart
All patients with STEMI in Sweden and Iceland undergoing
primary or rescue PCI. N=11 709 *)
Enrolled in TASTE
N=7259
Erroneous
enrollments
N=15
Not enrolled
N=4697
Randomized in TASTE
N=7244
N=3621 assigned
to thrombus aspiration
N=3623 assigned
to conventional PCI
N=3399 underwent
thrombus aspiration
N=222 underwent
conventional PCI
N=3445 underwent
conventional PCI
N=178 underwent
thrombus aspiration
N=3621 were
followed up
N=3623 were
followed up
N=1162 underwent
thrombus aspiration
N=1162 were
followed up
N=3535 underwent
conventional PCI
N=3535 were
followed up
TASTE
TASTE
TAPAS
JETSTENT
AIMI
INFUSE-AMI
VAMPIRE
PREPARE
Chevalier
Kaltoft
MUSTELA
X AMINE ST
PIHRATE
EXPIRA
DEAR-MI
Liistro
0
1000
2000
3000
4000
Number of patients
5000
6000
7000
8000
HR 0.94 (0.72 - 1.22), P=0.63
Per protocol analysis based
on actual treatment:
HR 0.88 (0.66 - 1.17), P=0.38
Fröbert, O. et al. N Engl J Med 2013; 369:1587-97
HR 0.61 (0.34 - 1.07), P=0.09
Per protocol analysis based
on actual treatment:
HR 0.67 (0.36 - 1.20), P=0.19
Not randomized in TASTE
Randomized in TASTE
PCI Only
Thrombus
Aspiration
Point Estimate
(95% confidence interval)
P Value
PCI Only
Thrombus
Aspiration
30 days
All cause death or myocardial infarction - no. (%)
140 (3.9)
121 (3.3)
HR 0.86 (0.67 - 1.10)
0.23
398 (11.6)
134 (11.8)
Stent thrombosis - no. (%)
19 (0.5)
9 (0.2)
HR 0.47 (0.20 - 1.02)
0.06
18 (0.5)
5 (0.4)
Target vessel revascularization - no. (%)
76 (2.2)
63 (1.8)
HR 0.83 (0.59 - 1.15)
0.27
80 (2.3)
30 (2.6)
Target lesion revascularization - no. (%)
57 (1.6)
43 (1.2)
HR 0.75 (0.51 - 1.12)
0.16
64 (1.8)
25 (2.2)
Stroke or neurological complication - no. (%)
18 (0.5)
19 (0.5)
OR 1.06 (0.55-2.02)
0.87
32 (0.9)
12 (1.0)
Perforation or tamponade - no.(%)
14 (0.4)
13 (0.4)
OR 0.93 (0.44-1.98)
0.85
13 (0.4)
7 (0.6)
Heart failure - no.(%)
234 (6.5)
245 (6.8)
OR 1.05 (0.87-1.27)
0.60
353 (10.0)
125 (10.8)
Index hospitalization
0.33
Left ventricular function - no. (%)
Moderately reduced, LVEF 30-39%
495 (13.7)
526 (14.5)
523 (14.8)
190 (16.4)
Severely reduced, LVEF <30%
157 (4.3)
137 (3.8)
255 (7.2)
102 (8.8)

This large, prospective, RRCT trial showed:
◦ no reduction of mortality at 30 days
◦ no significant reduction of hospitalization for MI or of
stent thrombosis at 30 days
◦ no reduction of other important clinical endpoints during
hospitalization

Our findings leave little role for manual thrombus aspiration
as a routine adjunct to PCI in STEMI

The RRCT concept may help to reverse the decline in
randomized trials in a cheap, fast and efficient way
SS Jolly, JA Cairns, S Yusuf, B Meeks, J Pogue, MJ Rokoss, S Kedev, L
Thabane,
G Stankovic, R Moreno, A Gershlick, S Chowdhary, S Lavi, K Niemelä, PG
Steg,
I Bernat, Y Xu, WJ Cantor, C Overgaard, C Naber, AN Cheema, RC
Welsh,
OF Bertrand, A Avezum, R Bhindi, S Pancholy, SV Rao, MK Natarajan,
JM ten Berg, O Shestakovska, P Gao, P Widimsky, V Džavík
on behalf of the TOTAL Investigators
STEMI* with Primary PCI ≤12 hours of symptom onset
Sample size of 10,700 for 80% power to detect a 20% Relative Risk
Reduction
1:1 Randomization between strategies
Routine Upfront Manual
Thrombectomy
followed by PCI
PCI Alone
(only bailout thrombectomy)
Primary Outcome: CV death, MI, cardiogenic shock and
class IV heart failure ≤180 days
Safety Outcome: Stroke ≤30 days
Bailout Thrombectomy allowed if PCI alone strategy fails:
• Persistent TIMI 0 or 1 flow with large thrombus after balloon predilatation
• Persistent large thrombus after stent deployment at target lesion
North
America
3863
Europe
5617
Asia
Pacific
865
South America
387
10,732 patients randomized between
August 2010 and July 2014
10,732 enrolled and
randomized
TOTAL
10,066 underwent PCI for
STEMI
5033 Manual
Thrombectomy
Crossover to
PCI alone
in 230 (4.6%)
5033 included in analysis
5030 PCI Alone
Cross-over to
Thrombectomy as
initial strategy in 69
(1.4%)
Bailout
Thrombectomy
in 355 (7.1%)
5030 included in analysis
Day 180
Thrombect
PCI alone
omy
95% CI
p
347 (6.9%) 351 (7.0%) 0.99
0.85-1.15
0.86
CV death
157 (3.1%) 174 (3.5%) 0.90
0.73-1.12
0.34
Recurrent MI
99 (2.0%)
92 (1.8%)
1.07
0.81-1.43
0.62
Cardiogenic Shock
92 (1.8%)
100 (2.0%) 0.92
0.69-1.22
0.56
90 (1.8%)
0.82-1.45
0.57
(N=5033) (%)
CV death, MI, shock or
class IV heart failure
Class IV heart failure 98 (1.9%)
(N=5030) (%)
HR
1.09
Thrombecto
my
(N=5033) (%)
Stroke within 30
days
Stroke or TIA within
30 days
Stroke within 180
days
PCI alone
(N=5030) (%)
HR
95% CI
p
33 (0.7%)
16 (0.3%)
2.0
1.13-3.75 0.015
6
42 (0.8%)
19 (0.4%)
2.21 1.29-3.80 0.003
52 (1.0%)
25 (0.5%)
2.08 1.29-3.35 0.002
Cumulative % of Stroke
2.0
Hazard ratio, 2.08 (95%CI, 1.29-3.35); P=0.0021
1.5
1.0
Thrombectomy
0.5
PCI alone
0
0
1
2
3
4
Months of Follow-up
5
6
Thrombecto
PCI alone
my
(N=5033) (%)
(N=5030) (%)
HR
95% CI
p
CV Death, MI, shock
or
class IV heart failure
281 (5.6%)
287 (5.7%)
0.98 0.83-1.15 0.79
Stent Thrombosis
59 (1.2%)
69 (1.4%)
0.85 0.60-1.21 0.37
Target Vessel
Revascularization
126 (2.5%)
132 (2.6%)
0.95 0.75-1.22 0.69

Routine thrombectomy compared to PCI alone
with only bailout thrombectomy did not reduce
CV death, MI, shock or heart failure within 180
days

Routine thrombectomy was associated with
increased risk of stroke within 30 days

TOTAL and TASTE emphasize the need to
conduct large randomized trials of common
interventions even when small trials appear
positive
MECHANICAL APPROACHES
On site
protection
•M Guard


Micro-Mesh Technology for Embolic Protection
Coronary Stent System
lumen
strut
neointima
intima
net
TVR
8.7%
6.0%
M Guard
MGuard -Weerackody et al.
5.8%
BMS
DES
Horizons - DES
Horizons - BMS
Primary and major secondary endpoints of MAGICAL Study*
92%
No Prior
Aspiration
82%
74% 73%
67%
Prior
Aspiration
57%
36%
27%
TIMI 3
MGB 3
Complete STR
TIMI 3 &
MGB 3 &
Complete STR
* ST resolution obtained from 46 patients due to technical issues
STEMI with symptom onset within 12 hours at
432 pts at 50 sites in 9 countries
R
Stratified by infarct vessel
and thrombus aspiration
PCI with BMS or DES
PCI with MGuard
Follow-up: 30 days, 6 months, 1 year
Primary endpoint: ST-segment resolution at 60-90 minutes
Substudies:
Cardiac MRI: 60 pts (30 pts in each arm) at 3-5 days
Angio FU: 50 pts in MGuard arm at 13 months
MGuard stent
(n=217)
Control stent
(n=214)
P value
4 (1.8%)
5 (2.3%)
0.75
– Cardiac mortality*
0 (0.0%)
4 (1.9%)
0.06
– Reinfarction
3 (1.4%)
2 (0.9%)
1.00
– TLR, ischemia-driven
4 (1.8%)
1 (0.5%)
0.37
TVR, ischemia-driven
6 (2.8%)
1 (0.5%)
0.12
Stent thrombosis, def/prob
3 (1.4%)
2 (0.9%)
1.00
Stroke
1 (0.5%)
0 (0.0%)
1.00
TIMI bleeding, major/minor
4 (1.8%)
4 (1.9%)
1.00
MACE
Mortality at 30 days occurred in 0/211 pts with complete STR and
in 4/198 pts with partial or absent STR (0% vs 2.0%, p=0.05)
* There were no non-cardiac mortalities
• Among pts with acute STEMI undergoing
emergent PCI, the MGuard micronet mesh
covered stent compared to conventional
metallic stents resulted in superior rates of
epicardial coronary flow and complete STR
• A larger randomized trial is warranted to verify
these findings, and determine whether these
benefits result in reduced infarct size and/or
improved clinical outcomes (MASTER II)
In the 2010 European Guidelines on Myocardial
revascularization, mesh-based protection, is now
recommended for use:
“Mesh-based protection may be considered for PCI of
highly thrombotic or SVG lesions” (class IIb/c recommendation)
Mesh based protection may be considered for PCI of highly thrombotic or SVG lesions
*European Heart Journal (31):2051-2555 -doi:10.1093/eurheartj/ehq277
M GUARD is approved by FDA for investigational use
MASTER II IDE regulatory trial 2013
MECHANICAL APPROACHES
On site
protection
• Self expanding
stent
• STENTYS
Self-expanding stents will reduce malapposition in
acute MI compared to balloon-expandable stents
resulting in less stent thrombosis at long term
follow-up
STENTYS Technology
• Nitinol, self-expanding stent
• Retractable sheath
• Low crossing profile
• 6F single-wire,
rapid exchange
• 22 or 27 mm length
DESIGN
Prospective, randomized, twoarm multicenter study
80 STEMI patients
randomized
between December 2009 and June 2010
in 9 European clinical sites
OBJECTIVE
To compare the STENTYS® Stent
with a balloon-expandable stent in
AMI
PRIMARY ENDPOINT
Stent strut apposition at 3 days by
OCT
STUDY ORGANIZATION
CEC, DSMB, Core Lab, Independent
monitoring
STENTYS®
43 pts
Control group
VISION/Driver
37 pts
OCT & QCA at 3 days
Clinical FU at 30
days and 6 months
53
•
C7 XR LightLab Imaging
•
Analysis by an independent Core lab (Cardialysis)
•
Analyzed region: stented segment plus 5 mm proximal and distal
•
Lumen and stent area were measured at 1 mm intervals
•
Malapposition defined as the distance between the leading edge of the
strut and the leading edge of the contour bigger than the strut thickness
Day 0
Self
Balloon
Expandable
Stent
Day 3
APPOSED
MALAPPOSED
54
Stent strut malapposition at 3 days
200-600 struts per patient
STENTYS
n = 40
Post PCI
2.20%
Control
n = 36
5.99%
P
Value
<0.05
Stentys
Control
8
7
P <0.001
5.99
6
3 days
0.51%
5.33%
<0.001
P <0.001
5.33
5
4
10-fold reduction in malapposition
with STENTYS self-expanding stent
3
2.20
2
1
0.51
0
Post-procedure
At 3 days
50
STENTYS
n = 40
Control
n = 36
P Value
0%
28 %
<0.001
Stentys
Control
40
P <0.001
30
DEFINITION MALAPPOSED
STENT:
≥ 5% MALAPPOSED STRUTS
28 %
20
10
0%
0
At 3 days
P. Barlis et al. Eur Heart J (2010) 31 (2): 165-176
56



Prospective, single-arm, multi-center study designed
To assess the long term performance of Stentys SelfApposing Stents in routine clinical practice in patients
suffering from ST-elevation myocardial infarction
(STEMI).
The primary endpoint,
◦ Major Adverse Cardiac Events rate (MACE, defined as cardiac death,
target vessel re-MI, emergent by-pass, or clinically-driven TVR) at one
year, was 9.3%, where conventional stents average 11.1% in a pooled
analysis from ACTION Study Group (Pitié-Salpêtrière Hospital, Paris).
◦ At the one-year time point, the cardiac death rate was 2%, as compared
with rates for conventional stents in other published trials which average
3.9%, the lowest rate being 2.2%.
Improved outcomes in patients with
Thrombus Burden in STEMI can be
achieved by:
1. Early and effective primary PCI
2. Reduction of thrombus load – upstream
DAPT, bail out ASPIRATION or Angiojet
3. Preventing embolization of thrombus debris
by onsite protection using newer stents