2. Viewed in 117 Countries

3. Complex Coronary Cases
Supported by:
Abbott Vascular
Boston Scientific Corporation
Medtronic, Inc.
Daiichi Sankyo, Inc. and Lilly USA, LLC

4. Disclosures
Samin K. Sharma, MBBS, FACC Speaker’s Bureau – Boston Scientific Corporation, Abbott, The Medicines Company, Daiichi Sankyo, Inc. and Lilly USA, LLC Annapoorna S. Kini, MBBS, FACC Nothing to disclose Sameer Mehta, MBBS, FACC Consulting Fees – The Medicines Company American College of Cardiology Foundation staff involved with this case have nothing to disclose

5. February 19th 2013 Case #8: HA, 60 yr M
Presentation:
Presented on 12/21/2012 with cresendo CCS class II angina and had stress echo revealing lateral and inferior ischemia. Cath revealed 2 V CAD and normal LV function. SYNTAX score 20. Patient had successful PCI using DES (EES) of LCx-HL and did well. Still has residual angina on moderate exertion.
Prior History:
Hyperlipidemia, Hypertension, +F/H, no prior MI, CML in remission
Medications: All once daily dosage
Aspirin 81mg, Clopidogrel 75mg, Nebivolol 5mg, Amlodipine 10mg, Simvastatin 40mg, Prednisone 20mg, Synthroid 25mcg 5

6. Case# 8: cont… SYNTAX score 20 Cardiac Cath 12/21/2012
2 Vessel with LVEF 70%
Left Main: Normal
LAD: <50% lesion in mid, rest mild diffuse disease
LCx: 90% ulcerated LCx-HL lesion, rest non- obstructive
RCA: 100% occlusion prox-mid segment with distal vessel
large and fills via bridge collaterals and via retrograde collaterals from LAD/LCX
Plan Today:
- PCI of prox RCA CTO via antegrade/retrograde approach 6

7. Appropriateness Criteria for Coronary Revascularization

8. Issues Involving The Case
Update on CTO recanalization
Status of platelet inhibition (PI) testing

9. Issues Involving The Case
Update on CTO recanalization
Status of platelet inhibition (PI) testing

10. Chronic Total Occlusion (CTO)
From Randomized Trials to Daily Practice
1. CTO is present in 20-22% of cath cases but PCI is attempted only in 5-13% of these cases
2. From BARI trial (1994) to SYNTAX trial (2007) , the single most common reason for a patient to be referred to surgery and not randomized was a CTO with low success rate of recanalization
3. Even in the recent era of increasing success rate of CTO recanalization (50-75%), the PCI success rate for CTO lesions in the SYNTAX trial was only 53%

11. Patients with chronic total occlusion (CTO)
Current Perspective on Coronary CTO The Canadian Multicenter CTO Registry
Patients with chronic total occlusion (CTO)
N = 1697 (18.4% of CAD pts on cath)
PCI
N = 515
30%
Medical therapy
N = 747
44%
CABG
N = 435
26%
Attempted CTO PCI
N = 162
10%
Management of CTO
Registry Patients
CTO bypassed
N = 388
23%
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Successful CTO PCI
N = 123 7%
Fefer et al, J Am Coll Cardiol 2012;59:991 11

12. Management of CTO Registry Patients by Treating Center
Current Perspective on Coronary CTO The Canadian Multicenter CTO Registry
Key Message: XIENCE V® provides the right combination of technology with a deliverable, efficacious, and safe platform.
Throughout this section you will present the key features of XIENCE V®, including the Multi-Link vision stent, the Multi-Link Vision stent delivery system, the everolimus elution profile, and the fluorinated copolymer. You will also show how these features work together to provide deliverability, efficacy, and safety.
Management of CTO Registry Patients by Treating Center
Fefer et al, J Am Coll Cardiol 2012;59:991 12

13. Chronic Total Occlusion (CTO)
Adverse Factors for PCI
Lower success rates: disappointment
Longer cases: disrupts the schedule
More radiation exposure: dermatitis
More resource utilization: without reimbursement
Minimal incidence but potentially catastrophic complications: thrombus, dissection, perforation, cardiac tamponade, collaterals shut off, side-branch occlusion, Contrast Induced AKI, MI, uCABG

14. Patel et al., JACC Cardiovasc Interv 2013;6:12814

15. Temporal Trends in Cumulative Angiographic Success Rates and Major Procedural Complication Rates
Patel et al., JACC Cardiovasc Interv 2013;6:128 15

16. Incidence of Angiographic Success and
Procedural Complications in CTO PCI %
Patel et al., JACC Cardiovasc Interv 2013;6:128 16

17. Incidence of Procedural Complications in Successful vs
Incidence of Procedural Complications in Successful vs. Unsuccessful CTO PCI
Outcome
Successful
Unsuccessful
p Value
MACE (%)
3.7
4.3
0.68
Death (%)
0.4
1.5
<0.001
Emergent CABG (%)
0.03
0.17
0.74
Stroke (%)
0.07
0.04
Myocardial Infarction (%)
2.8
3.0
0.87
Q-wave MI (%)
0.3
0.5
0.26
Coronary perforation (%)
10.7
Tamponade (%)
0.0
1.7
Vascular complication (%)
0.9
0.20
Contrast nephropathy (%)
5.0
4.6
0.86
Patel et al., JACC Cardiovasc Interv 2013;6:128 17

18. Chronic Total Occlusion (CTO) Rationales for CTO Recanalization
Relief of angina and ischemia
Improvement in LV function
Reduced need for CABG at long-term
Improvement in survival

19. Meta-Analysis of CTO Outcomes
13 Observational Studies, 7288 patients weighted averaged follow-up 6 years
OR for Success
vs. Failure
95% Cl
p Value
Mortality
0.56
<0.001 MI
0.74
0.26
Subsequent CABG
0.22
Residual Angina
0.45
0.001
Joyal et al., Am Heart J 2010;160:179. 19

20. Effect of Successful vs
Effect of Successful vs. Failed CTO PCI in All-Cause Mortality During Long-Term Follow-up
Author, Year
Yr Follow-up
PCI Success (n)
PCI Failure (n)
OR/HR, 95% CI
Finci, et al., 1990 2
100
OR: 1.70,
Warren et al., 1990
2.6 26 18
N/A
Ivanhoe et al., 1992 4
317
163
OR: 0.21,
Angioi et al., 1995
3.6 93
108
OR: 0.37,
Noguchi et al., 2000
4.3
134 92
OR: 0.28, 0.11 – 0.72
Suero et al., 2001 10
1,491
514
OR: 0.67, 0.54 – 0.83
Olivari et al., 2003 1
289 87
OR: 0.19, 0.03 – 1.14
Hoye et al., 2005
4.5
567
304
OR: 0.52, 0.32 – 0.84
Drozd et al., 2006
2.5
298
161
OR: 0.74, 0.23 – 2.37
Aziz, et al.,2007
1.7
377
166
OR: 0.31, 0.13 – 0.76
Prasad et al., 2007
914
348
OR: 0.82, 0.62 – 1.08
Valenti et al., 2008
344
142
OR: 038, 0.19 – 0.77
de Labriolle et al., 2008
127 45
OR: 1.25, 0.25 – 6.27
Mehran et al., 2011
2.9
1,226
565
HR: 0.63, 0.40 – 1.0
Jones et al., 2012
3.8
582
254
HR: 0.28, 0.15 – 0.52
Joyal et al., 2010
5,056
2,236
OR: 0.56, 0.43 – 0.72
Moses et al., JACC Cardio Interv 2012;5:389 20

21. Successful Recanalization of CTO Associated with Improved Long-Term Survival
18.2%
6.5%
Jones et al., JACC Cardio Interv 2012;5:380 21

22. Successful Recanalization of CTO Associated with Improved Long-Term Survival
Jones et al., JACC Cardio Interv 2012;5:380. 22

23. Long-Term Outcome of CTO PCI
Independent Predictors of Mortality, MI and CABG up to 5 year F/U HR
95% CI
p Value
Independent predictors of mortality
CKD
2.72
<0.01
Diabetes mellitus
2.02
Age (per-yr increment)
1.09
Procedural success of CTO
0.63
0.05
Independent predictors of MI
2.50
0.03
Independent predictors of CABG
CTO located in LAD
1.88
0.01
Hypercholesterolemia
0.56
0.02
Procedural Success of CTO
0.21
Mehran et al. J Am Coll Cardiol Inv 2011;4:952

24. Change of Lumen Area Between Baseline
and 6 Months After CTO Recanalization
Park et al., JACC Card Interv 2012;5:827 24

25. Recanalization of CTO Leads to Lumen Area
Increase in Distal Reference Segments
2.24
2.45
2.91
3.05
4.0
4.87
6.85
7.65
Park et al., JACC Card Interv 2012;5:827 25

26. Retrograde Wire Technique of CTO Recanalization

27. Retrograde Techniques for CTO Recanalization
Typically reserved for LAD or RCA CTOs via septal collaterals; avoid using epicardial collaterals
Four techniques:
Direct retrograde crossing
Kissing wire
Controlled Antegrade and Retrograde Subintimal Tracking (CART); balloon dilatation or knuckle wire
Reverse CART, LaST

28. Retrograde Wire Technique for Chronic Total Occlusion Recanalization
Four Patterns of Success in Retrograde CTO Recanalization
Sumitsuji et al. J Am Coll Cardiol Intv 2011;4:941.

29. Surmely JF, J Invasive Cardiol. 2006;18:334
Concept of CART Technique Controlled Antegrade and Retrograde Subintimal Tracking
Surmely JF, J Invasive Cardiol. 2006;18:334

30. Temporal Trends In Technical Success of Retrograde CTO PCI in Multicenter Registry
Karmpaliotis et al., JACC Cardio Interv 2012;5:1273 30

31. Summary of Published Retrograde CTO PCI Series
Study
Year N
Prior CABG %
Septal Collaterals Used %
Reverse CART, %
Technical Success %
Major Complications %
Flouroscopy Time, min, mean ± SD
Contrast Use, ml mean ± SD
Sianos, et al.
2008
175
10.9
79.4 NR
83.4
4.6
59 ± 29
421 ± 167
Rathore et al.
2009
157
17.8
67.5
84.7
4.5
Kimura et al.
224
17.6
79.0
14.0
92.4
1.8
73 ± 42
457 ± 199
Tsuchikane et al.
2010 93
10.8
82.8
60.9
98.9
0.0
60 ± 26
256 ± 169
Morino et al.
136
9.6
63.9
79.2
US Registry
2012
462
50.0
71.0
41.0
81.4
2.6
61 ±
345 ± 177
Karmpaliotis et al., JACC Cardio Interv 2012;5:1273 31

32. The procedure involves five key steps:
Retrograde PCI: 5 Steps
Retrograde PCI for recanalization of CTOs has gained acceptance as a necessary technique to improve success
The procedure involves five key steps:
Wiring of the collateral from the donor artery into the distal bed of the recipient artery, usually with the use of hydrophilic jacketed guidewires
Delivery of over-the-wire microcatheters or balloons to allow an exchange for a CTO-specific guidewire
Crossing the total occlusion with the CTO guidewire and dilating the CTO with the retrograde balloon
Placing an antegrade guidewire into the distal bed through the recanalized CTO
5. Stenting the lesion

33. Retrograde Wire Technique for CTO Recanalization
When to do Retrograde technique?
Minimum 200 CTO cases via antegrade technique
Dedicated setup, equipments and ability to handle complications
Usually after failed antegrade (once or twice) approach
Ostial stump occlusion (RCA, LAD, LCx)

34. Propensity Score-Matched Event Rates by Stent Type for CTO PCI: 30-Month Follow up
DES (n=8,218)
BMS (n=2,043)
p = 0.04
p = 0.72 %
p = 0.74
p = 0.51
Patel et al., J Am Coll Cardio Intv 2012;5:1054 34

35. CTO PCI: First Generation DES vs. EES
First-generation DES (n=294)
EES (n=294)
p = 0.001
p = <0.001
p = 0.023 %
p = 0.002
p = 0.007
p =
p = 0.082 35

36. PRISON III Trial: Cypher vs. ZES-Resolute
SES (n=103)
ZES-Resolute (n=104) %
Teeuwen et al., TCT 2012 36

37. CIBELES Trial: Clinical and Angio Follow-up
SES (n=101)
EES (n=106)
p=NS for all comparison
(trended lower with Xience) %
p=0.34
Moreno et al. TCT 2012 37

38. Fundamental Wire Technique and Current Strategy for Chronic Total Occlusion PCI
Procedural Steps of Current CTO-PCI
Cotralateral
Dual Injection
CTO - PCI
Single Wire Technique
Antegrade approach x2
Parallel Wire Technique
Retrograde approach (ostial)
Retrograde Wire Cross
Kissing Wire Cross
IVUS guide re-entry
CART
Reverse CART
Success
Failure

39. Issues Involving The Case
Update on CTO recanalization
Status of platelet inhibition (PI) testing

40. Impact of On-Treatment Platelet Reactivity
Post-PCI Ischemic/Thrombotic Clinical Events
Bonello et al., J Am Coll Cardiol 2010;56:919 40

41. High On-Treatment Platelet Reactivity
in the Setting of PCI
PRI >50% by VASP analysis
>230 to 238 P2Y12 reaction units by VerifyNow assay
>46% maximal 5-µmol/1 ADP-induced aggregation
>468 arbitrary aggregation units/min in response to ADP by Multiplate analyzer 41

42. Incidence of in-hospital major bleeding (5)
Incidence of In-hospital TIMI Bleed in Patients with Enhanced Response to Clopidogrel (AU <188) vs. Remaining Patients (AU >188)
Incidence of in-hospital major bleeding (5)
2.2
p = 0.005
0.8
Enhanced Remaining
responders (n=975) patients (n=1558)
Sibbing et al., J of Thrombosis & Haemostasis 2009;8:250

43. Platelet Reactivity and Clinical Outcome MACE Rates by PRU Quartiles
Barr et al., J Am Coll Cardiol 2011;58:1945 43

44. Clinical Studies Based Platelet Reactivity Measurement by VerifyNow Assay
GRAVITAS
TRIGGER-PCI
ARCTIC
DANTE – 75mg vs 150mg Clopidogrel daily
TOPAS -1 – 600mg loading and 75mg daily for 6
months with prior PCI
6. ANTARCTIC – patients > 75 years 44

45. GRAVITAS Study Design Elective or Urgent PCI with DES* R
VerifyNow P2Y12 Test hours post-PCI by Accumetrics
PRU ≥ 230 R
High-Dose Clopidogrel†
clopidogrel 600-mg, then
clopidogrel 150-mg daily X 6 months
Standard-Dose Clopidogrel†
clopidogrel 75-mg daily X 6 months
Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo
Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo
Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months
*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at hrs
†placebo-controlled
All patients received aspirin (81-162mg daily)
Price et al. JAMA 2011;305:1097.

46. GRAVITAS Trial: Primary Endpoint: CV Death, MI, Stent Thrombosis4 3
2.3% vs. 2.3%
HR 1.01 (95% CI 0.58 – 1.76)
p=0.98
CV death, non-fatal MI, or ST %
Cumulative Incidence of 2 1
High-Dose Clopidogrel
Standard-Dose Clopidogrel 30 60 90
120
150
180
210
No. at Risk
High Dose Clopidogrel
Standard Dose Clopidogrel
Observed event rates are listed; P value by log rank test.
Price et al. JAMA 2011;305:1097.

47. TRIGGER PCI Trial: Study Design
Elective PCI with DES without GP IIb/IIIa use
VerifyNow P2Y12 Test 2-4hrs first clopidogrel MD (75mg)
N= 2150
PRU ≥ 206
All patients received aspirin (81-162mg daily) R
Prasugrel
Loading dose 60mg, then 10mg daily X 6 months
Placebo LD,then Clopidogrel 75mg daily X 6 months
Primary Efficacy Endpoint: CV Death, Non-Fatal MI at 6 mo
Key Safety Endpoint: Moderate or Severe Bleeding at 6 mo
Pharmacodynamics: Repeat VerifyNow P2Y12 at 3 and 6 months
Trial was halted after 432 pts enrolled because of <2% event rate (projected 7%) in 250 pts reaching 6M mark

48. Cumulative Composite Incidence of Efficacy Bleeding Events
TRIGGER-PCI Study
Cumulative Composite Incidence of Efficacy Bleeding Events
PAI Data
Trenk et al., JACC 2012;59:2159 48

49. ARCTIC Study: Randomization before planned PCI with DES (n = 2500)
Monitoring Treatment Arm
1- Systematic assessment of PD response to clopidogrel + aspirin pre-DES and between day
14 and day 30
2-Adjustment of DAPT dose regimen* if high on-treatment platelet reactivity pre-DES
3-Adjustment of DAPT dose regimen if hyper/hyporesponder during the maintenance phase
Conventional Arm
1- No monitoring of PD response
2- DAPT strategy at physician discretion according to routine practice
Assessment of the primary endpoint at 1 year (minimal follow-up of 6 months for the last patients)
All-cause mortality MI
All urgent revascularization
Stent thrombosis requiring revascularization or not
Ischemic stroke requiring a new hospitalization
DAPT =dual antiplatelet therapy
*In the absence of high platelet reactivity (HPR), MD regimen is aspirin 75 mg + clopidogrel 75 mg. 49

50. ARCTIC STUDY
Collet et al., NEJM 2012;367:2100 50

51. ARCTIC STUDY: Incidence of High-On Treatment Platelet Reactivity in the Monitoring Group%
Collet et al., NEJM 2012;367:2100

52. Antiplatelet Therapy in ARCTIC Study Conventional Treatment (N=1227)
Monitoring (N=1213)
p Value
Clopidogrel
Before randomization – (%)
89.5
88.5
0.42
After randomization
High platelet reactivity – (%) NA
34.5 -
Loading dose at time of procedure – (%)
10.2
25.3
<0.001
Prasugrel
Before randomization – (%)
0.7
0.6
0.63
0.3
1.2
0.01
Thienopyridine at discharge – (%)
Any
99.3
98.7
0.15
93.5
89.4
0.003
5.8
9.3
0.001
Aspirin
98.2
96.7
0.70
High platelet reactivity (%)
7.6
Intravenous loading dose or Additional bolus of
ASA in patients with a poor response (%)
84.8
At discharge, in any form or dose – (%)
0.17
GP Ilb/IIIa use – (%)
6.1
30.1
Collet et al., NEJM 2012;367:2100 52

53. Antiplatelet Therapy in ARCTIC Study Conventional Treatment (N=1227)
Monitoring (N=1213)
p Value
Thienopyridine at f/u between days (%)
High platelet reactivity NA
15.6
Increase in clopidogrel maintenance dose in
patients with a poor response
43.0
Prasugrel maintenance dose
6.0
12.1
<0.001
Aspirin at f/u visit between days (%)
3.9
Increase in maintenance dose in patients with
a poor response
45.7
Treatment at last visit (%)
Clopidogrel
86.4
80.0
Prasugrel
6.1
11.9
Aspirin
96.1
96.0
0.87
Collet et al., NEJM 2012;367:2100 53

54. ARCTIC STUDY: Incidence of High-On Treatment Platelet Reactivity in the Monitoring Group%
Collet et al., NEJM 2012;367:2100

55. ARCTIC Trial: Monitoring Antiplatelet Therapy for Coronary Stenting
Proportion of Patients with Primary Outcome Events (death, MI, stroke/TIA, uRevasc, ST) and Main Secondary Outcome Events (ST, uRevasc) at 1 Year F/U
34.6%
31.1%
Collett et al., NEJM 2012:367:2100. 55

56. ARCTIC Trial: Monitoring Antiplatelet Therapy for Coronary Stenting
Study End Points at 1 Year Follow-up*
Conventional Treatment (n=1227)
Monitoring (n=1213)
p = 0.10
p = 0.32 %
p = 0.28
p = 0.77
p = 0.76
p = 0.08
p = 0.24
p = 0.51
Primary Secondary Death Death MI Stent Urgent Major or
End Point End Point recurrent ACS, thrombosis revasc Minor
stroke, TIA bleeding
* Patients could have more than one end point
Collett et al., NEJM 2012:367:2100. 56

57. Clinical Studies Based Platelet Reactivity Measurement by VerifyNow Assay
GRAVITAS
TRIGGER-PCI
ARCTIC
DANTE – 75mg vs 150mg Clopidogrel daily
TOPAS 1 – 600mg loading and 75mg daily for 6
months with prior PCI
6. ANTARCTIC – patients >75 years 57

58. Routine Testing for Platelet Inhibition by VerifyNow Assay Instrument (Accumetrics)
Assessment of platelet
aggregation inhibition (PI):
- Goal; Optimal response – PRU
<230 in maintenance phase on
chronic ADP receptor blockers
?PRU 208
- Management if PRU >230;
- Make sure about compliance
- PPI interaction
- ? Genetic testing for
2C19*2 allele polymorphism
- If on plavix, then either
switch to Prasugrel (30mg LD
& 5-10mg MD or double
plavix dose to 150mg daily)

59. Take Home Message: Update on CTO Recanalization and Status of Platelet Inhibition Studies
Successful CTO recanalization in appropriately selected cases has shown to improve survival with minimal procedural complications. EES has shown superior results compared to first generation DES with lower reocclusion and repeat restenosis
Studies utilizing platelet inhibition measurement guided more intense antiplatelet therapy, have not shown to change MACE outcomes post PCI. Hence routine PI measurement has very limited value in clinical practice.

60. Question # 1
Successful CTO recanalization is associated with the following except :
Improved survival
Lower CABG
Lower acute complications
Improved LV function
E. Reduced angina

61. Question # 2
Following features are associated with high success rates of successful CTO recanalization except:
Tapered tip
Calcification
Good visualization of distal vessel
Sidebranch at the site of occlusion
E. No bridge collaterals

62. Question # 3
Following are the PCI studies utilizing platelet inhibition measurement guiding antiplatelet therapy except:
ARCTIC trial
GRAVITAS trial
TRIGGER-PCI trial
DANTE trial
PLATO trial

63. Question # 1
Successful CTO recanalization is associated with the following except :
Improved survival
Lower CABG
Lower in-hospital MACE
Improved LV function
E. Reduced angina
The correct answer is C. Recent meta-analysis of published CTO trials showed better survival, lower need for CABG, reduced angina and improved LV function after successful CTO recanalization. But there was no difference in acute MACE.
Patel et al., JACC Cardiovasc Interv 2013;6:128

64. Question # 2
Following features are associated with high success rates of CTO recanalization except:
Tapered tip
No calcification
Good visualization of distal vessel
Sidebranch at the site of occlusion
E. No bridge collaterals
The correct answer is D. Presence of a sidebranch at the site of CTO is associated with high failure rates while other features are favorable for successful recanalization.

65. Question # 3
Following are the PCI studies utilizing platelet inhibition measurement guiding antiplatelet therapy except:
ARCTIC trial
GRAVITAS trial
TRIGGER-PCI trial
DANTE trial
PLATO trial
The correct answer is E. PLATO trial compared Clopidogrel to Ticagrelor and did not utilize platelet inhibition measurement to guide the therapy. ARCTIC, GRAVITAS and TRIGGER-PCI trials measured platelet inhibition to guide therapy but were negative. DANTE trial comparing 75mg vs. 150mg clopidogrel in poor responders, is ongoing