giuseppe biondi zoccai interventional cardiology, university of turin, italy [email protected]...

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?

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

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


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


increased peri-PCI risk in diffuse disease?


in patients with diffuse disease?



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


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

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


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

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

For further slides on these topics please feel free to visit the metcardio.org website:

http://www.metcardio.org/slides.html









giuseppe biondi zoccai interventional cardiology, university of turin, italy [email protected]...

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