Giuseppe Biondi ZoccaiGiuseppe Biondi Zoccai
Interventional Cardiology, University of Turin, ItalyInterventional Cardiology, University of Turin, Italy
[email protected]@gmail.com
PCI in diabetics and diffuse PCI in diabetics and diffuse
disease: role of IIb/IIIa inhibitorsdisease: role of IIb/IIIa inhibitors
• Co-principal investigator in an
upcoming trial on eptifibatide (GSK)
• No other conflicts of interest or
funding to declare
DisclosureDisclosure
Scope of the problem Scope of the problem in DM and diffuse CADin DM and diffuse CAD
Diffuse Diffuse diseasedisease
Resistance to
Resistance to
antiplatelet agents
antiplatelet agents
Incomplete Incomplete
revascularization
revascularization
Risk of side branch Risk of side branch
compromisecompromise
Success (?)Success (?)
Prothrombotic Prothrombotic milieaumilieau
Overlapping DESOverlapping DES
Risk of dissectionRisk of dissection
Herrmann,EHJ 2005
Etiology of peri-procedural necrosisEtiology of peri-procedural necrosis
Herrmann, EHJ 2005
Predictors of peri-procedural necrosisPredictors of peri-procedural necrosis
Modulating factorsModulating factors
Herrmann, EHJ 2005
Does peri-procedural Does peri-procedural necrosis matter at all?necrosis matter at all?
Cavallini, EHJ 2005
• 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?
What is the role of IIb/IIIa What is the role of IIb/IIIa inhibitors in PCI of diabetics?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?
What is the role of IIb/IIIa What is the role of IIb/IIIa inhibitors in PCI of diabetics?inhibitors in PCI of diabetics?
Biondi-Zoccai, JACC 2003
Multiple detrimental mechanismsMultiple detrimental mechanisms
Platelet activationPlatelet activation
Myers, BUMC Proceedings 2005
Aspirin resistanceAspirin resistance
Hankey, Lancet 2006
Clopidogrel resistanceClopidogrel resistance
Nguyen, JACC 2005
CYPHERCYPHER
n = 873n = 873
TAXUSTAXUS
n = 447n = 447
p valuep value
Death, %Death, % 0.4 0.4 00 0.310.31
Myocardial InfarctionMyocardial Infarction
Q wave MI, %Q wave MI, % 0.10.1 0.70.7 0.100.10
Non Q wave MI, %Non Q wave MI, % 11.011.0 10.410.4 0.720.72
Re PCI, %Re PCI, % 2.22.2 1.11.1 0.16 0.16
In hospital CABG, %In hospital CABG, % 0.70.7 0 0 0.180.18
Acute ST, %Acute ST, % 0.10.1 0.5 0.5 0.220.22
In-Hospital MACE
• 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?
What is the role of IIb/IIIa What is the role of IIb/IIIa inhibitors in PCI of diabetics?inhibitors in PCI of diabetics?
Meta-analysis of RCTMeta-analysis of RCT
Reduction in mortality @ 1 monthReduction in mortality @ 1 month
Karvouni, JACC 2003
Survival benefit in DM & ACSSurvival benefit in DM & ACS
Roffi, Circ 2001
ADVANCE trialADVANCE trial
Valgimigli, JACC 2004
Any doubt?Any doubt?
ISAR-SWEET trial
DES deployed in
only 10% of pts
Mehilli, Circ 2004
BARE31.9% Abc40.2% PlaP=0.04
DES7.3% Abc4.9% PlaP=NS
ISAR-SWEET ISAR-SWEET
Mehilli, Circ 2004
Paradoxical results of TAXUS IVParadoxical 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 >3 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 >3 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
ISAR-REACT 2 trialISAR-REACT 2 trial
DES deployed
in 50% of pts
Kastrati, JAMA 2006
Prevention of intraprocedural Prevention of intraprocedural drug-eluting stent thrombosisdrug-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 ratio=0.24 [95% confidence interval 0.06 to 0.97], p=0.036).
Biondi-Zoccai, AJC 2005
Biondi-Zoccai, AJC 2005
0,54
0
0,45
0
0,49
00
0,2
0,4
0,6
0,8
1
Chieffo et al(N=915)
RECIPE(N=1320)
Pooled estimate(N=2235)
no IIb/IIIa
IIb/IIIa
%%Odds ratio=0.24 p=0.034Odds ratio=0.24 p=0.034
Prevention of intraprocedural Prevention of intraprocedural drug-eluting stent thrombosisdrug-eluting stent thrombosis
• 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?
What is the role of IIb/IIIa What is the role of IIb/IIIa inhibitors in PCI of diabetics?inhibitors in PCI of diabetics?
• 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?
What is the role of IIb/IIIa inhibitors What is the role of IIb/IIIa inhibitors in PCI of diffuse disease?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?
What is the role of IIb/IIIa inhibitors What is the role of IIb/IIIa inhibitors in PCI of diffuse disease?in PCI of diffuse disease?
Impact of plaque burdenImpact of plaque burden
Porto, Circ 2006
Predictors of intraprocedural stent Predictors of intraprocedural stent thrombosis in the RECIPE Studythrombosis in the RECIPE Study
Biondi-Zoccai, AJC 2005
IPST No IPST
Variable n=6 n=1314 P
Multiple stenting in the same lesion 3 (50%) 155 (12%) 0.027
Total stent length per vessel 50±42 27±21 0.047
Baseline minimum lumen diameter 0.35±0.35 0.79±0.46 0.021
Hazards of multivessel Hazards of multivessel DES implantation DES implantation
Orlic, JACC 2004
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
Overlapping DESOverlapping DES
TAXUS V- the impact on side branches TAXUS V- the impact on side branches in the overlap region (per side branch)in the overlap region (per side branch)
Control TAXUS
51/20351/203 68/20768/207 12/4812/48 26/5526/55
Any TIMI FlowAny TIMI FlowReductionReduction
Non-overlapNon-overlap
regionregion
OverlapOverlap
regionregion
25.1 25.0
32.9
47.3
p=0.10 p=0.025
Possible Causes for TIMI Flow Reduction?•Plaque burden & “snowplow” effect•Jailing of the side branch
Impact of increased strut width
Macro Strut Width •TAXUS 120 µm•Express2 90 µm
•33% increase in total strut width
Hazards of overlapping DES Hazards of overlapping DES implantation in diffuse diseaseimplantation in diffuse disease
Tsagalou, JACC 2005
• 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?
What is the role of IIb/IIIa inhibitors What is the role of IIb/IIIa inhibitors in PCI of diffuse disease?in PCI of diffuse disease?
Mortality at 30 days
Karvouni, JACC 2003
Role of IIb/IIIa inhibitors in ACS
Consisting of peri-procedural IIb/IIIa inhibitors (p=0.041)
and/or thienopyridines (p=0.091)
Biondi-Zoccai, Am Heart J 2005
Prevention of acute drug-Prevention of acute drug-eluting stent thrombosiseluting stent thrombosis
Biondi-Zoccai, AJC 2005
0,54
0
0,45
0
0,49
00
0,2
0,4
0,6
0,8
1
Chieffo et al(N=915)
RECIPE(N=1320)
Pooled estimate
no IIb/IIIa
IIb/IIIa
%%Odds ratio=0.24 P=0.034Odds ratio=0.24 P=0.034
• 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?
What is the role of IIb/IIIa inhibitors What is the role of IIb/IIIa inhibitors in PCI of diffuse disease?in PCI of diffuse disease?
Herrmann, EHJ 2005
Additional treatmentsAdditional treatments
++
+/-+/-
++++++
++++++++
+/-+/-
+/-+/-
Superiority of a high (Superiority of a high (>>600 mg) 600 mg) clopidogrel loading doseclopidogrel loading dose
Outcome:Outcome: One-month death or myocardial infarction One-month death or myocardial infarction
Study High loading Low loading Peto OR Peto ORor 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 applicableTest 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
What about bivalirudin?What about bivalirudin?Outcome: Death/MI/recurrent ischemia
Study DTI Control Peto OR Peto ORor 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 ORor 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
So what is the state of the art treatment?So what is the state of the art treatment?
FREEDOMFREEDOM
MV-stentingMV-stentingWith DES and ReoProWith DES and ReoPro
Eligibility : DM patients with MV-CAD eligible for stent or surgeryEligibility : DM patients with MV-CAD eligible for stent or surgeryExclude : Patients with acute STEMI, cardiogenic shockExclude : Patients with acute STEMI, cardiogenic shock
CABGCABGWith or without CPBWith or without CPB
All concomitant Meds shown to be beneficial are encouraged, including : All concomitant Meds shown to be beneficial are encouraged, including : Plavix, ACE inhibitors,Plavix, ACE inhibitors, -blockers, statins etc-blockers, statins etc
PRIMARY: 5-year mortalityPRIMARY: 5-year mortalitySECONDARY: 12-month MACCE, 5-year Quality of LifeSECONDARY: 12-month MACCE, 5-year Quality of Life
Randomized 1:1
Integrilin plus STenting to Integrilin plus STenting to
Avoid myocardial Necrosis TrialAvoid myocardial Necrosis Trial
PI: G. Sangiorgi, A. Colombo
Co-PI: G. Biondi Zoccai
ISTANT trialISTANT trial
Randomization
Eptifibatide double IV bolus Matched placebo
In-hospital follow-up
One-month follow-up
Six-month follow-up
Coronary angiogram showing significant nativecoronary lesion treatable by means of >33 mm of DES
Administration of 600 mg clopidogrel loading and heparin bolus in the catheterization laboratory
Take home messages Take home messages for successful PCI for successful PCI
• 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
Take home messagesTake home messages
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