Adjunctive Therapy Adjunctive Therapy for PCIfor PCI

Neal Uren MD MRCPDepartment of Cardiology

Royal Infirmary of Edinburgh

Determinants of Successful Determinants of Successful PCIPCI

CLINICAL STATUSCLINICAL STATUS LV function Stable vs. unstable angina vs. MI

LESION COMPLEXITYLESION COMPLEXITY AHA/ACC class

OPERATOR VOLUMEOPERATOR VOLUME

ADJUNCTIVE THERAPYADJUNCTIVE THERAPY Stenting (BENESTENT, STRESS) Anti-thrombotic and anti-platelet agents

RationaleRationale

““Although it is not yet possible to Although it is not yet possible to pharmacologically modify the risk pharmacologically modify the risk of balloon-mediated intimal and of balloon-mediated intimal and medial disruption, it is possible medial disruption, it is possible

to modify chemically the platelet-to modify chemically the platelet-fibrin response to vascular injury fibrin response to vascular injury in order to influence the outcome in order to influence the outcome

of the procedure”of the procedure”

Pharmacological Pharmacological Adjunctive TherapyAdjunctive Therapy

Heparin

Aspirin

Clopidogrel

Glycoprotein IIb/IIIa inhibitors

UK Interventional UK Interventional Practice 1999Practice 1999

Structured questionnaire

68% response over 4 months

53% ≥10,000 U heparin

8.3% abciximab use

82% clopidogrel use

Swanson N et al, Int J Cardiol 2001;79:119-125

HeparinHeparin Lower incidence of complications in unstable angina

patients pre-treated with iv heparin Lukas MA et al, JACC 1988;11:132A(abstr)

Close temporal relationship between discontinuation of anticoagulation after PTCA and coronary occlusion Gabliani G et al, AHJ 1988;116:696-700

10,000 U iv heparin = ACT <300s in 5% of stable and 15% of unstable patients Dougherty KG et al, CCD 1992;26:260-3

Defining the Optimal ACTDefining the Optimal ACT with UF Heparinwith UF Heparin

Meta-analysis of 6 trials with UFH as control

n=5216, with patients in 25 s intervals

Endpoint of 7 day MACE + major/minor bleeds

ACT 350-375 s 6.6% vs ACT 171-295 s 8.8% (p<0.01)

ACT should be substantially higher than currently appreciated

Chew DP et al, Circulation 2001;103:961-6

Low Dose Heparin Low Dose Heparin (30 U/kg)

n=418 patients

Mean age 63±11 years

2253±1056 U/l with a final ACT of 174±69 s

Manual compression for 7.7±3 minutes

Average procedure time of 25±16 minutes

MACE 2.9% at discharge

0.24% serious vascular complications Godon P et al, Arch Mal Coeur Vaiss

2001;94:984-8

Low Molecular Weight Low Molecular Weight HeparinHeparin

Elective PCI

NICE 1 = enoxaparin 1.0 mg/kg iv

NICE 4 = enoxaparin 0.75 mg/kg iv with standard abciximab

Comparable incidence of bleeding and ischaemic complications in NICE 4 compared with UFH + abciximab

Kereiakes DJ et al, J Invas Cardiol 2001;13:272-8

Low Molecular Weight Low Molecular Weight Heparin Heparin

2 doses of Dalteparin + abciximab (n=57)

0

2

4

6

8

10

12

Procedural thrombosis Major bleeding

40 U/kg60 U/kg

Kereiakes DJ et al, Am Heart J 2001;141:348-52

AspirinAspirin No difference in outcome between 80 mg and

1500 mg started 24 h pre-PCI Mufson L et al, JACC

1988;11:236A(abstr)

No additional benefit of dipyridamole Lembo NJ et al, AJC 1990;65:422-6

No benefit from single dose ASA pre-PCI

Patrono C et al, Circulation 1985;72:1177-84

Ticlopidine Study TrialTiclopidine Study Trial

0

2

4

6

8

10

12

14 Placebo

ASA 325mg2 +Persantin 75 mg3

Ticlopidine 250 mg3

Perc

en

tag

e

Ischaemic complications after 4-5 days pre-treatment

White CW et al, Circulation 1987;76:IV-400

* p=0.06

Platelet Aggregability Platelet Aggregability Post-PCIPost-PCI

0

20

40

60

80

100

120

Pre Post

ASA+Ticlid PTCAASA Coronary angio

**

p=0.06p=0.03

Tim

e t

o o

cclu

sion

(s)

Greateraggregability

Fischetti D et al, J Thromb Thrombolysis 2001;10:265-9

De-evolution of Stent De-evolution of Stent ThrombosisThrombosis

1986-91 Serruys et al/Schatz et al~25%1991 10 pooled studies4.5%1993 Stress/Benestent/TASC 1 3.7%1994 Colombo et al

0.9%1995 MUST Registry

1.6%1996 MUSIC Registry

0.6%1997 Moussa et al1.9%

Risk of MACE After Successful StentingRisk of MACE After Successful Stenting

• • • • •• • • •

• AgeAge • DiabetesDiabetes• Acute MI (<72h)Acute MI (<72h)• Unstable anginaUnstable angina• Impaired LVImpaired LV• Stented length• Residual dissection• Stent overlapStent overlap •Use of ticlopidine*

Schülen et al, Circulation 1998;98:104-111

0.1 1.0 10 200.1 1.0 10 20Hazard Ratio & 95% CIHazard Ratio & 95% CI

n=2894n=2894105 events105 events

* 80% ASA+Ticlidopine

•

•

•

•

•

•

• CFX or SVGCFX or SVG • Vessel sizeVessel size• Stenosis gradeStenosis grade• Stenosis lengthStenosis length• Acute occlusion pre-stentAcute occlusion pre-stent• Experience Experience (yrs)(yrs)

0.1 1.0 10 200.1 1.0 10 20

Odds Ratio & 95% CIOdds Ratio & 95% CI

Risk of a Procedural FailureRisk of a Procedural Failure

Schülen et al, Circulation 1998;98:104-111

Procedure failure = MACE 42.6%, procedure success = MACE 3.6%

The STARS Trial

0

1

2

3

4

5

6

7

Stent Thrombosisat 30 days

Haemorrhagiccomplications

AspirinAspirin+WarfarinAspirin +TiclopidineP

erc

en

tag

e

*

* p<0.001 vs. others

*

1965 patients50 centres

84% angio. success

Leon MB et al, NEJM 1998;339:1702-4

The STARS Trial Suboptimal Stent Registry

0123456789

30 day stentthrombosis

30 daymortality

Peri-procedure

NQWMI

Optimal (<10%DS)Suboptimal

265 patients16% vs.27% 9/12 CRS*

**

* p<0.01

Perc

en

tag

e

Cutlip DE et al, JACC 1999;34:698-706

Clopidogrel vs. Ticlopidine Clopidogrel vs. Ticlopidine Post-PCIPost-PCI

No one trial large enough to demonstrate comparability

n=13,995 meta-analysis 1° endpoint of MACE at 30 days after

stenting MACE clopidogrel = 2.1% vs MACE ticlopidine =

4.0% Death clopidogrel = 0.48% vs death ticlopidine

= 1.1%

Bhatt Dl et al, JACC 2002;39:9-14

MACE Post-StentingMACE Post-Stenting

Bhatt Dl et al, JACC 2002;39:9-14

30 Day Mortality Post-30 Day Mortality Post-StentingStenting

Bhatt Dl et al, JACC 2002;39:9-14

Duration of TherapyDuration of TherapyRetrospective analysis of ticlopidine post-stentn=56782.0% stent failure at 2 weeks + 0.5% at 2-4 weeks Risk factors for late events (2.5% if all 3

present)

- age- reduced LV function- hypertension

4 weeks theinopyridine therapy preferable

Schülen H et al, JACC 37:2066-73

Timing of TherapyTiming of Therapy

Ticlopidine >24 h pre-PCI cause significant platelet inhibition

Maximum effect at 3-5 days van de Loo A et al, Eur Heart J

1998;19:96-102

Ticlopidine pre-treatment duration ~ reduced NQWMI

Steinbuhl S et al, JACc 1998;32:1366-70

Clopidogrel induces platelet inhibition within 30 min

MACE ~ no pre-treatment (T / C) [OR 3.5]

Steven P et al, JACC 2001;38:648A (abstr)

n=2099 n=2972 n=1265

Glycoprotein IIb/IIIa Receptor Glycoprotein IIb/IIIa Receptor InhibitionInhibition

30 day MACE with Abciximab30 day MACE with Abciximab

0PlaceboReopro B+I

EPICEPIC EPILOGEPILOG CAPTURECAPTUREHigh-risk PCI Refractory

USA pre-PCI

0

5

10

15

20

15.9%

11.3%

2

4

6

8

10

12

14

12.8%

8.3%

NEJM1994;330:957 NEJM 1997;336:1689 Lancet 1997;349:1429

11.7%

5.3%

Perc

en

tag

e

Low dose heparin = 70 U/kg for ACT≥200 s

Stnadard dose heparin = 100 U/kg for ACT≥300 s

EPILOG & Bleeding RiskEPILOG & Bleeding Risk

EPILOG & Bleeding RiskEPILOG & Bleeding Risk

MACE in the CAPTURE trial by TnTMACE in the CAPTURE trial by TnT

Hamm CW et al, NEJM 1999;340:1623

63 centres in North America 2399 patients undergoing PCI 36% unstable angina <48h 57% unstable angina <6 months 16% recent MI (<7 days) 20% diabetics Reopro 60 min pre-PCI, 12 h post-PCI

Lancet 1998;352:87

The EPISTENT TrialThe EPISTENT Trial

EPISTENT at 30 Days and 12 MonthsEPISTENT at 30 Days and 12 Months

0

5

10

15

20

30 day

MACE

Stent + placebo

Stent + abciximab

Balloon + abciximab

TVR

1 year

* p<0.01, ° p<0.05

Death/MI

**

*°

*

%

Death/MI/Urgent Revascularisation

Lancet 1998;352:87

EPISTENT Subgroup AnalysisEPISTENT Subgroup Analysis

Lancet 1998;352:87

EPISTENT Subgroup AnalysisEPISTENT Subgroup AnalysisReduction of Non-Q wave MIReduction of Non-Q wave MI

Lancet 1998;352:87

ESPRITESPRIT

ESPRITESPRIT

ESPRITESPRIT

Heparin - lower doses acceptable (?<5000 U)

Pre-treatment with aspirin essential Clopidogrel pre- & post-stenting GpIIb/IIIa receptor inhibitors - Reopro™

reduces CK release in stable angina No substitute for optimal stent

deployment

ConclusionsConclusions