Giuseppe Biondi Zoccai

1
PCI in diabetics and diffuse disease role of
IIb/IIIa inhibitors

• Giuseppe Biondi Zoccai
• Interventional Cardiology, University of Turin,
  Italy
• gbiondizoccai_at_gmail.com

2
Disclosure

• Co-principal investigator in an upcoming trial on
  eptifibatide (GSK)
• No other conflicts of interest or funding to
  declare

3
Scope of the problem in DM and diffuse CAD
Risk of side branch compromise
Overlapping DES
Resistance to antiplatelet agents
Risk of dissection
Prothrombotic milieau
Diffuse disease
Incomplete revascularization
Success (?)
4
Etiology of peri-procedural necrosis
Herrmann, EHJ 2005
5
Predictors of peri-procedural necrosis
Herrmann, EHJ 2005
6
Modulating factors
Herrmann, EHJ 2005
7
Does peri-procedural necrosis
matter at all?
Cavallini, EHJ 2005
8
What is the role of IIb/IIIa inhibitors in PCI of
diabetics?

• What is the pathophysiology underlying the
  increased peri-PCI risk of diabetics?
• What is the evidence base on of IIb/IIIa
  inhibitors in diabetics undergoing PCI?
• Which additional treatments should be recommended
  in diabetics or diffuse CAD?

9
What is the role of IIb/IIIa inhibitors in PCI of
diabetics?

• What is the pathophysiology underlying the
  increased peri-PCI risk of diabetics?
• What is the evidence base on of IIb/IIIa
  inhibitors in diabetics undergoing PCI?
• Which additional treatments should be recommended
  in diabetics or diffuse CAD?

10
Multiple detrimental mechanisms
Biondi-Zoccai, JACC 2003
11
Platelet activation
Myers, BUMC Proceedings 2005
12
Aspirin resistance
Hankey, Lancet 2006
13
Clopidogrel resistance
Nguyen, JACC 2005
14
In-Hospital MACE
C vs. T REWARD (Diabetic Sub-study)
CYPHER n 873 TAXUS n 447 p value
Death, 0.4 0 0.31
Myocardial Infarction
Q wave MI, 0.1 0.7 0.10
Non Q wave MI, 11.0 10.4 0.72
Re PCI, 2.2 1.1 0.16
In hospital CABG, 0.7 0 0.18
Acute ST, 0.1 0.5 0.22
15
What is the role of IIb/IIIa inhibitors in PCI of
diabetics?

• What is the pathophysiology underlying the
  increased peri-PCI risk of diabetics?
• What is the evidence base on of IIb/IIIa
  inhibitors in diabetics undergoing PCI?
• Which additional treatments should be recommended
  in diabetics or diffuse CAD?

16
Meta-analysis of RCT
17
Reduction in mortality _at_ 1 month
Karvouni, JACC 2003
18
Survival benefit in DM ACS
Roffi, Circ 2001
19
ADVANCE trial
Valgimigli, JACC 2004
20
Any doubt?
21
ISAR-SWEET trial
DES deployed in only 10 of pts
Mehilli, Circ 2004
22
ISAR-SWEET
BARE 31.9 Abc 40.2 Pla P0.04
DES 7.3 Abc 4.9 Pla PNS
Mehilli, Circ 2004
23
Paradoxical results of TAXUS IV
Impact of Platelet Glycoprotein IIb/IIIa Inhibition on the Paclitaxel-Eluting Stent A TAXUS IV Substudy
Ideal anti-thrombotic strategy in patients undergoing percutaneous coronary interventions (PCI) is still a matter of controversy. A number of studies have shown that while a combination of glycoprotein IIb/IIIa inhibitors with weight adjusted heparin improves anti-ischemic efficacy (particularly decreasing peak CK-MB iso-enzyme elevation after PCI) it still increases the vascular complications after the procedure. Use of bivalirudin may prove equally efficacious (also in reducing peak CK-MB elevation) without increasing the risk of bleeding. However, it is limited by issues of non-reversibility of bivalirudin effect. However, these data have not been rigorously tested in the era of drug eluting stents. Teirstein and co-workers performed a prespecified subgroup analysis of the TAXUS IV study population to examine the effect of procedural glycoprotein IIb/IIIa inhibition during paclitaxel-eluting stent implantation on periprocedural creatine kinase-MB (CK-MB) levels. Glycoprotein (GP) IIb/IIIa inhibitors were administered to 57.7 of patients who had been randomized to receive the TAXUS stent and to 56.7 of those who had been randomized to receive the control stent. Among patients who received the TAXUS stent, the rate of CK-MB increases of gt3 times the normal level was 2.6-fold higher in those who received a GP IIb/IIIa inhibitor than in those who did not (11.4 vs 4.4, p 0.0015). Composite rates of major adverse cardiac events and target vessel failure were also higher at 1 month in the GP IIb/IIIa group. By multivariate analysis, use of GP IIb/IIIa inhibitors during stenting with the TAXUS stent was an independent predictor of CK-MB increases gt3 times the normal level. However, the issue is far from closed, further studies are warranted to confirm the present findings and to look for the mechanisms of the same.

Teirstein, Am J Cardiol 2005
24
ISAR-REACT 2 trial
DES deployed in 50 of pts
Kastrati, JAMA 2006
25
Prevention of intraprocedural drug-eluting stent
thrombosis
The occurrence of intra-procedural stent
thrombosis (IPST) was analyzed across 1,320
patients undergoing drug-eluting stenting in 4
Italian centers. IPST occurred in 6 (0.5), with
in-hospital major adverse events in 4 (67). By
pooling results of the present study with those
of a previous study, for a total of 2,235
patients, elective glycoprotein IIb/IIIa
inhibitors appeared to significantly prevent the
occurrence of IPST, because no IPST occurred
among patients treated with glycoprotein IIb/IIIa
inhibitors (0 of 725), whereas all IPST occurred
in the absence of adequate upfront IIb/IIIa
inhibition treatment (11 of 1,510 0.7, odds
ratio0.24 95 confidence interval 0.06 to
0.97, p0.036).
Biondi-Zoccai, AJC 2005
26
Prevention of intraprocedural drug-eluting stent
thrombosis

Odds ratio0.24 p0.034
Biondi-Zoccai, AJC 2005
27
What is the role of IIb/IIIa inhibitors in PCI of
diabetics?

• What is the pathophysiology underlying the
  increased peri-PCI risk of diabetics?
• What is the evidence base on of IIb/IIIa
  inhibitors in diabetics undergoing PCI?
• Which additional treatments should be recommended
  in diabetics or diffuse CAD?

28
What is the role of IIb/IIIa inhibitors in PCI of
diffuse disease?

• What is the pathophysiology underlying the
  increased peri-PCI risk in diffuse disease?
• What is the evidence base on of IIb/IIIa
  inhibitors in patients with diffuse disease?
• Which additional treatments should be recommended
  in diabetics or diffuse CAD?

29
What is the role of IIb/IIIa inhibitors in PCI of
diffuse disease?

• What is the pathophysiology underlying the
  increased peri-PCI risk in diffuse disease?
• What is the evidence base on of IIb/IIIa
  inhibitors in patients with diffuse disease?
• Which additional treatments should be recommended
  in diabetics or diffuse CAD?

30
Impact of plaque burden
Porto, Circ 2006
31
Predictors of intraprocedural stent thrombosis in
the RECIPE Study
IPST No IPST Variable n6 n1314
P Multiple stenting in the same
lesion 3 (50) 155 (12) 0.027 Total
stent length per vessel 5042 2721
0.047 Baseline minimum lumen diameter
0.350.35 0.790.46 0.021
Biondi-Zoccai, AJC 2005
32
Hazards of multivessel DES
implantation
But CK-MB 3xULN in 26 (16.8) patients
specifically 17 12.8 with 2VD SES implantation
and in 9 32.1 patients with 3VD SES
implantation
Orlic, JACC 2004
33
Overlapping DES
34
TAXUS V- the impact on side branches in the
overlap region (per side branch)
Control
TAXUS

• Possible Causes for TIMI Flow Reduction?
• Plaque burden snowplow effect
• Jailing of the side branch
• Impact of increased strut width

Any TIMI Flow Reduction
p0.10
p0.025

• Macro Strut Width
• TAXUS 120 µm
• Express2 90 µm
• 33 increase in total strut width

51/203
68/207
12/48
26/55
Non-overlap region
Overlap region
35
Hazards of overlapping DES implantation in
diffuse disease
Tsagalou, JACC 2005
36
What is the role of IIb/IIIa inhibitors in PCI of
diffuse disease?

• What is the pathophysiology underlying the
  increased peri-PCI risk in diffuse disease?
• What is the evidence base on of IIb/IIIa
  inhibitors in patients with diffuse disease?
• Which additional treatments should be recommended
  in diabetics or diffuse CAD?

37
Mortality at 30 days
Karvouni, JACC 2003
38
Role of IIb/IIIa inhibitors in ACS
Consisting of peri-procedural IIb/IIIa inhibitors
(p0.041) and/or thienopyridines (p0.091)
Biondi-Zoccai, Am Heart J 2005
39
Prevention of acute drug-eluting stent thrombosis

Odds ratio0.24 P0.034
Biondi-Zoccai, AJC 2005
40
What is the role of IIb/IIIa inhibitors in PCI of
diffuse disease?

• What is the pathophysiology underlying the
  increased peri-PCI risk in diffuse disease?
• What is the evidence base on of IIb/IIIa
  inhibitors in patients with diffuse disease?
• Which additional treatments should be recommended
  in diabetics or diffuse CAD?

41
Additional treatments
/-




/-
/-
Herrmann, EHJ 2005
42
Superiority of a high (gt600 mg) clopidogrel
loading dose
Outcome
One-month death or myocardial infarction


Study
High loading
Low loading
Peto OR
Peto OR
or sub-category
n/N
n/N
95 CI
95 CI
01 Randomized trials
ALBION
2/68 1/35
1.03 0.09, 11.50
ARMYDA-2
5/126 15/126
0.34 0.14, 0.84
CLEAR PLATELETS
1/60 3/60
0.36 0.05, 2.61
Cuisset
6/146 13/146
0.46 0.18, 1.15
Subtotal (95 CI)
400 367
0.41 0.23, 0.75
Total events 14 (High loading), 32 (Low loading)
Test for heterogeneity Chi² 0.79, df 3 (P
0.85), I² 0
Test for overall effect Z 2.90 (P 0.004)
02 Non-randomized studies
Wolfram
13/319 4/126
1.28 0.44, 3.74
Subtotal (95 CI)
319 126
1.28 0.44, 3.74
Total events 13 (High loading), 4 (Low loading)
Test for heterogeneity not applicable
Test for overall effect Z 0.45 (P 0.66)
Total (95 CI)
719 493
0.54 0.32, 0.91
Total events 27 (High loading), 36 (Low loading)
Test for heterogeneity Chi² 4.03, df 4 (P
0.40), I² 0.8
Test for overall effect Z 2.31 (P 0.02)
0.01
0.1
1
10
100
Favours high loading
Favours low loading
Biondi-Zoccai, submitted
43
What about bivalirudin?
Outcome
Death/MI/recurrent ischemia


Study
DTI
Control
Peto OR
Peto OR
or sub-category
n/N
n/N
95 CI
95 CI
01 Bivalirudin vs heparin plus provisional or
routine GPIIbIIIa inhibitors
ACUITY
356/4604 334/4603
1.07 0.92, 1.25
CACHET
4/174 6/94
0.32 0.09, 1.21
PROTECT-TIMI 30
51/284 82/574
1.32 0.89, 1.96
REPLACE-1
26/532 30/524
0.85 0.49, 1.45
REPLACE-2
227/2986 211/3000
1.09 0.90, 1.32
Subtotal (95 CI)
8580 8795
1.07 0.96, 1.20
Total events 664 (DTI), 663 (Control)
Test for heterogeneity Chi² 5.04, df 4 (P
0.28), I² 20.7
Test for overall effect Z 1.25 (P 0.21)
0.5
0.7
1
1.5
2
Favours DTI
Favours control
Outcome
Death/MI/recurrent ischemia/major bleeding


Study
DTI
Control
Peto OR
Peto OR
or sub-category
n/N
n/N
95 CI
95 CI
01 Bivalirudin vs heparin plus provisional or
routine GPIIbIIIa inhibitors
ACUITY
541/4604 538/4603
1.01 0.89, 1.14
PROTECT-TIMI 30
52/284 86/574
1.28 0.87, 1.88
REPLACE-1
38/532 46/524
0.80 0.51, 1.25
REPLACE-2
275/2975 299/2990
0.92 0.77, 1.09
Subtotal (95 CI)
8395 8691
0.98 0.89, 1.08
Total events 906 (DTI), 969 (Control)
Test for heterogeneity Chi² 3.36, df 3 (P
0.34), I² 10.7
Test for overall effect Z 0.39 (P 0.70)
0.5
0.7
1
1.5
2
Favours DTI
Favours control
Abbate, submitted
44
So what is the state of the art treatment?
45
FREEDOM
46
Integrilin plus STenting to Avoid myocardial
Necrosis Trial
PI G. Sangiorgi, A. Colombo Co-PI G. Biondi
Zoccai
47
ISTANT trial
Coronary angiogram showing significant
native coronary lesion treatable by means of gt33
mm of DES
Randomization
Administration of 600 mg clopidogrel loading and
heparin bolus in the catheterization laboratory
In-hospital follow-up
One-month follow-up
Six-month follow-up
48
Take home messages for
successful PCI
49
Take home messages

• Gp IIb/IIIa inhibitors provided significant
  benefits in diabetics treated with PTCA or BMS
• The introduction of high-dose clopidogrel loading
  has significantly improved peri-procedural
  outcomes, and likely limited the use of Gp
  IIb/IIIa inhibitors to selected cases (ie
  high-risk and/or ACS)
• Their impact in diabetics undergoing PCI in the
  DES era has not yet been thoroughly established,
  but lack of evidence for an effect cannot be
  considered evidence for lack of an effect
• Given the absence of specific data on diffuse
  disease, precise inference in this setting will
  have to wait for ongoing and future trials

50
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