Adjunctive Therapy for PCI

1. Adjunctive Therapy for PCI Neal Uren MD MRCP Department of Cardiology Royal Infirmary of Edinburgh

2. Determinants of Successful PCI CLINICAL STATUS • LV function • Stable vs. unstable angina vs. MI LESION COMPLEXITY • AHA/ACC class OPERATOR VOLUME ADJUNCTIVE THERAPY • Stenting (BENESTENT, STRESS) • Anti-thrombotic and anti-platelet agents

3. Rationale “Although it is not yet possible to pharmacologically modify the risk of balloon-mediated intimal and medial disruption, it is possible to modify chemically the platelet-fibrin response to vascular injury in order to influence the outcome of the procedure”

4. Pharmacological Adjunctive Therapy • Heparin • Aspirin • Clopidogrel • Glycoprotein IIb/IIIa inhibitors

5. UK Interventional Practice 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

6. Heparin • 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

7. Defining the Optimal ACT with 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

8. 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

9. Low Molecular Weight Heparin • 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

10. Low Molecular Weight Heparin 2 doses of Dalteparin + abciximab (n=57) 12 10 8 40 U/kg 6 60 U/kg 4 2 0 Procedural thrombosis Major bleeding Kereiakes DJ et al, Am Heart J 2001;141:348-52

11. Aspirin • 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

12. Ticlopidine Study Trial Ischaemic complications after 4-5 days pre-treatment Placebo 14 ASA 325mg2 +Persantin 75 mg3 12 Ticlopidine 250 mg3 10 8 Percentage 6 4 2 0 White CW et al, Circulation 1987;76:IV-400

13. Platelet Aggregability Post-PCI * p=0.06 p=0.06 120 p=0.03 * Greater aggregability 100 * 80 Time to occlusion (s) 60 40 ASA+Ticlid PTCA 20 ASA Coronary angio 0 Pre Post Fischetti D et al, J Thromb Thrombolysis 2001;10:265-9

14. De-evolution of Stent Thrombosis 1986-91 Serruys et al/Schatz et al ~25% 1991 10 pooled studies 4.5% 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 al 1.9%

15. Risk of MACE After Successful Stenting • Age • n=2894 105 events • Diabetes • • • Acute MI (<72h) • Unstable angina • Impaired LV • • Stented length • • Residual dissection • • • Stent overlap • • • Use of ticlopidine* 0.1 1.0 10 20 0.1 1.0 10 20 Hazard Ratio & 95% CI Hazard Ratio & 95% CI * 80% ASA+Ticlidopine Schülen et al, Circulation 1998;98:104-111

16. Risk of a Procedural Failure Procedure failure = MACE 42.6%, procedure success = MACE 3.6% CFX or SVG • • Vessel size • • Stenosis grade • • Stenosis length • • Acute occlusion pre-stent • • Experience (yrs) • • 0.1 1.0 10 20 0.1 1.0 10 20 Odds Ratio & 95% CI Odds Ratio & 95% CI Schülen et al, Circulation 1998;98:104-111

17. The STARS Trial 1965 patients 50 centres 84% angio. success 7 6 5 Percentage 4 Aspirin 3 Aspirin+Warfarin * Aspirin +Ticlopidine 2 * 1 0 Stent Thrombosis at 30 days Haemorrhagic * p<0.001 vs. others complications Leon MB et al, NEJM 1998;339:1702-4

18. The STARS Trial Suboptimal Stent Registry 265 patients 16% vs.27% 9/12 CRS * 9 8 7 Multiple stents Low final MLD No ticlopidine 6 5 Percentage * 4 Optimal (<10%DS) 3 Suboptimal * 2 1 0 30 day stent thrombosis 30 day Peri- * p<0.01 mortality procedure NQWMI Cutlip DE et al, JACC 1999;34:698-706

19. Clopidogrel vs. Ticlopidine Post-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

20. MACE Post-Stenting Bhatt Dl et al, JACC 2002;39:9-14

21. 30 Day Mortality Post-Stenting Bhatt Dl et al, JACC 2002;39:9-14

22. Duration of Therapy • Retrospective analysis of ticlopidine post-stent • n=5678 • 2.0% 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

23. Timing 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)

24. Placebo Reopro B+I Glycoprotein IIb/IIIa Receptor Inhibition30 day MACE with Abciximab EPICEPILOGCAPTURE High-risk PCIRefractory USA pre-PCI 14 20 12.8% 12 35% 11.7% 29% 15 15.9% 10 8 Percentage 8.3% 55% 10 11.3% 6 5.3% 4 5 2 0 0 n=2099 n=2972 n=1265 NEJM1994;330:957 NEJM 1997;336:1689 Lancet 1997;349:1429

25. EPILOG & Bleeding Risk Low dose heparin = 70 U/kg for ACT≥200 s Stnadard dose heparin = 100 U/kg for ACT≥300 s

26. EPILOG & Bleeding Risk

27. MACE in the CAPTURE trial by TnT Hamm CW et al, NEJM 1999;340:1623

28. The EPISTENT Trial • 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

29. EPISTENT at 30 Days and 12 Months Death/MI/Urgent Revascularisation * 20 Stent + placebo 15 51% 52% Stent + abciximab % Balloon + abciximab 10 ° * * * * p<0.01, ° p<0.05 5 0 30 day MACE Death/MI TVR 1 year Lancet 1998;352:87

30. EPISTENT Subgroup Analysis Lancet 1998;352:87

31. EPISTENT Subgroup Analysis Reduction of Non-Q wave MI Lancet 1998;352:87

32. ESPRIT

33. ESPRIT

34. ESPRIT

35. Conclusions • 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