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Simon Redwood KCL St Thomas’ Hospital

ST Elevation ACS Adjunctive Therapy. Simon Redwood KCL St Thomas’ Hospital. Trials of Abciximab and PTCA versus PTCA. EPIC Post-Hoc Analysis - AMI subgroup: Am J Cardiol 1996; 77: 1045-51 RAPPORT: Circulation 1998; 98: 734-41. EPIC - Post-Hoc Analysis - AMI Subgroup.

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Simon Redwood KCL St Thomas’ Hospital

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  1. ST Elevation ACSAdjunctive Therapy Simon RedwoodKCLSt Thomas’ Hospital

  2. Trials of Abciximab and PTCA versus PTCA • EPIC Post-Hoc Analysis - AMI subgroup: • Am J Cardiol 1996; 77: 1045-51 • RAPPORT: Circulation 1998; 98: 734-41

  3. EPIC - Post-Hoc Analysis - AMI Subgroup Death, MI or TVR through 6 Months 64 patients (of 2099) 50 Placebo (n = 23) 47.8% 40 32.3% 30 Abciximab Bolus Only (n = 19) % of Patients  91% p = 0.002 20 10 Abciximab Bolus + Infusion (n = 22) 4.5% 0 0 1 2 3 4 5 6 Months adapted from AJC 1996; 77:1045-51

  4. EPIC - Post-Hoc Analysis - AMI subgroup Conclusions • Post-Hoc analysis indicates that Abciximab offers profound and robust benefit in primary PCI compared to primary PCI alone • Based on these results prospective trials were designed to evaluate the efficacy of Abciximab in Primary PCI (RAPPORT trial)

  5. RAPPORT ReoPro in AMI; Primary PCI Organization and Randomized Trial Circulation 1998; 98:734-41

  6. AMI < 12 hours; candidates for 1° PTCA n = 483 patients from 36 centres between 11/95 and 2/97 RAPPORT - Study Design Randomised on a double-blind basis Placebo 100 U/kg UFH Maintain ACT > 300s Abciximab (B + I)* 100 U/kg UFH Maintain ACT > 300s 1° Endpoint: D/MI/TVR through 6 months 2° Enpoints D/MI/Urgent TVR through 7 and 30 days * 0.25 mg/kg bolus with 0.125 g/kg/min infusion (max 10 g/min) Circulation 1998; 98:734-41

  7. Event Rates through 6 months - Intention to Treat 50 Placebo RAPPORT - Primary Endpoint p = 0.90 40 Abciximab 28.1 28.2 30 p = 0.048 % of Patients 17.8 20 11.6 10 n = 242 n = 241 n = 242 n = 241 0 Death/MI/Urgent TVR2 Death/MI/Any TVR1 Circulation 1998; 98:734-41 1 Primary Endpoint; 2 Secondary Endpoint

  8. Event Rates through 30 Days - Intention to Treat 25 Placebo RAPPORT - Secondary Endpoints 20 Abciximab p = 0.004 15 12.0 p = 0.006 % of Patients p = 0.52 10 7.9 5.8 4.6 4.6 5 1.8 n = 242 n = 241 n = 242 n = 241 n = 242 n = 241 0 Death/MI/Urgent TVR Re-MI Urgent TVR* Circulation 1998; 98:734-41 * TVR within 24 hrs for severe recurrent ischaemia

  9. RAPPORT Conclusions • Abciximab given during primary PTCA for MI did not alter the primary endpoint at 6 months which included elective revascularisation procedures • Abciximab given during primary PTCA for MI did decrease death / reinfarction / urgent revascularisation at day 7, 30 and 6 months • Abciximab reduced the need for bailout stenting • 20.4% vs 11.9%, p = 0.008, 42% reduction • Abciximab + primary PTCA shows better efficacy than primary PTCA alone

  10. Trials of Stenting versus PTCA • PAMI-STENT: NEJM 1999; 341: 1949-56 • CADILLAC: JACC 2001; 37 (Suppl. A): 343A and TCT 2000; Oral presentation

  11. PAMI-STENT Primary Angioplasty in Myocardial Infarction STENT NEJM 1999; 341: 1949-56

  12. PAMI-STENT Study design Randomised, multicentre 900 patients with acute myocardial infarction undergoing emergency catheterisation and angioplasty Angioplasty with stenting* (n = 452) Angioplasty alone (n = 448) * Heparin coated PS153 6-months composite endpoint Death/Re-MI/disabling stroke/TVR NEJM 1999; 341: 1949-56

  13. PAMI-STENT 6-months results PTCA Stent + PTCA p < 0.01 p = 0.02 20.1 16.9 % of patients 12.6 11.3 p = 0.27 4.2 2.7 Incidence of Angina Death Death/Re-MI / disabling stroke/TVR

  14. Stent PTCA p-value n 452 448 Angio. restenosis (6.5 mos) 23.5% 35.4% <0.0001 Ischaemic TVR (6 months) 10.6% 21.0% <0.0001 TIMI-3 flow final (operator) 92.9% 96.4% 0.02 TIMI-3 flow final (core lab) 89.5% 92.7% 0.046 Mortality (12 months) 5.4% 3.0% 0.054 Stent Heparin coated PS-153 Abciximab 5.8% 4.5% NS PAMI-STENT

  15. PAMI-STENT Conclusions • Implantation of a stent for acute myocardial infarction has clinical benefits beyond those of primary coronary angioplasty alone (decreased restenosis and TVR) • Despite improvements in ischaemic and restenotic endpoints, stented patients had a non significant trend for higher mortality after one year versus PTCA alone (5.4% vs 3.0%, p =0.054) • But: longer time to presentation (120 vs 110 mins p = 0.03) • bulky PS 153 • low abciximab use • Stent shows better efficacy than PTCA, although the mortality is questionable

  16. CADILLAC Controlled Abciximaband Device Investigationto Lower Late Angioplasty Complications

  17. Protocol Schematic (open label) Acute myocardial infarction Primary PTCA + No abciximab Primary PTCA + Abciximab MultiLink stent + No abciximab MultiLink stent + Abciximab 12 month clinical follow-up 7 month follow-up angiographic subset Primary endpoint - 6 month composite incidence of death, reinfarction, disabling stroke, or ischaemic TVR

  18. CADILLAC - Place/Time of Administration No Pre-Catheterisation Abciximab The lesion may be crossed with the guidewire prior to the abciximab bolus;PTCA should be performed as soon as the bolus is complete and prior to the start of the infusion.

  19. Stent No Abx (n = 512) Stent Abx (n = 525) PTCA No Abx (n = 516) PTCA Abx (n = 529) 60 61 60 61 28-96 24-94 22-90 29-91 72.4 74.1 71.4 73.8 16.2 19.3 15.4 16.7 48.3 44.1 43.1 50.4 36.8 36.8 35.5 40.0 44.8 44.4 41.7 43.3 30.7 31.7 30.8 33.2 CADILLAC - Baseline Characteristics Variable Age (Median, yrs) range Male(%) Diabetes (%) Hypertension (%) Hyperlipidemia (%) Current Smoker (%) Family History (%) p = NS for all TCT 2000; Oral Presentation

  20. PTCA alone PTCA + Abx Stent alone Stent + Abx Primary Endpoint-MACE through 6 Months 25 * not a pre-specified primary endpoint component 20 no p value given p = 0.001 19.3 15 % of Patients 15.2 10 10.8* 10.9 5 0 Death, re-MI, Ischaemic TVR or Disabling Stroke TCT 2000; Oral Presentation

  21. PTCA alone PTCA + Abx Stent alone Stent + Abx Endpoint Components Through 6 Months 20 p < 0.0001 * 14.2 15 p = 0.12 12.1 10 % of Patients p = 0.043 7.4 5.0 4.3 3.8 5 2.8 2.3 2.3 2.1 1.7 1.6 1.2 1.2 0.8 0.8 0 Death Reinfacrtion Disabling Stroke Ischaemic TVR * p = 0.002 vs. stent alone

  22. 30 Day Subacute Thrombosis PTCA alone PTCA + Abx Stent alone Stent + Abx 2.0 All stent + abciximab comparisons are post-hoc 1.7 p = 0.07 1.0 Incidence (%) 1.0 P=0.03 0.6 0.0 0.0

  23. Stent No Abx (n = 512) Stent Abx (n = 525) PTCA No Abx (n = 516) PTCA Abx (n = 529) 2.98 3.00 2.98 2.97 2.34* 2.37* 2.17 2.13 20.7* 20.0* 26.6 26.9 1.6 1.4 1.0 1.6 93.8 96.1 94.9 96.1 CADILLAC – Core Lab Results Variable QCA Ref Diameter MLD Diameter stenosis (%) TIMI Flow TIMI 0/1 TIMI 3 * p < 0.01 vs PTCA TCT 2000; Oral Presentation

  24. Conclusions • Similar to PAMI-STENT, stents resulted in a marked improvement in EFS compared to PCTA alone patients • Unlike PAMI-STENT, stents DID NOT result in decreased TIMI-3 flow or survival compared to PTCA • In patients undergoing PTCA, abciximab was associated with reduced mortality and improved EFS • However, no major long-term clinical benefits of abciximab were seen in patients undergoing routine stenting

  25. CADILLAC - Potential Problems • Crossover to ReoPro in placebo arm • 9.1% with PTCA, 6.1% with stent • Low overall incidence of events (Ref 2.5-4mm, 3mm less than stent length, no tortuosity or marked Ca2+ ) • Definition of (re-) MI • ReoPro not blinded • Primary endpoints were: Stent vs PTCA (no ReoPro), and Stent vs PTCA (with ReoPro), NOT ReoPro vs Placebo • More diabetics in ReoPro and stent arms

  26. Trials of Stent and Abciximab versus Stent alone • ISAR-2: JACC 2000; 35: 915-21 • ADMIRAL: NEJM 2001; 344: 1895-903

  27. ISAR-2 Intracoronary Stentingand Antithrombotic Regimen JACC 2000: 35:915-21

  28. intra- arterial UFH g/min for 12 hours 10 ISAR - II - Study Design stent AMI within 48 hours with planned placement; Prior to Cath: UFH 5,000 U and 500 mg IV ASA 1:1 Randomisation Abciximab Usual Care 0.25 mg/kg bolus Additional 10,000 U of followed by a continuous infusion of + + 1,000 U/hr for the 1st 12 Additional 2,500 U of hours post-sheath removal* intra-arterial UFH* (n = 201) (n = 200) Clinical Outcomes through 30 days JACC 2000: 35:915-21

  29. 25 Usual Care (n = 200) 20 Abciximab (n = 201)  52% ISAR II - Outcomes through 30 Days p = 0.038 15  58%  40% % of Patients  55% 10.5 p = 0.08 p = 0.3 p = 0.16 10  66% 6.0 5.0 5.0 p = 0.62 4.5 5 3.0 2.5 2.0 1.5 0.5 0 Death, MI or Any TVR Death or MI Death MI TVR JACC 2000: 35:915-21

  30. ADMIRAL Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long Term Follow-up NEJM 2001; 341:1895-1903

  31. Placebo + Stent Abciximab* + Stent UFH 70 U/kg (max. 7,000 U) followed by 7 U/kg/hr (maintain aPTT between 1.5-2.0 X control value) until the 24 hour follow-up angiogram completed Ticlopidine (250 mg; twice daily for 30 days post PCI) ADMIRAL - Trial Schematic (n = 300) ST , < 12 h Admission ASA Post-PCI 4 coronary angiograms 24 h Post-PCI 1º endpoint: Death, re-MI or urgent TVR through 30 days 2º endpoint: Death, re-MI or any revasc. through 30 days and 6 months 6 m Post-PCI NEJM 2001; 341:1895-1903

  32. Abciximab n = 149 Placebo n = 151 59.6 62.1 85.2 78.2 15.4 19.9 34.2 41.1 14.1 7.3 2.0 0.0 7.4 9.3 18.1 10.0 10.0 13.3 ADMIRAL - Demographics p-value 0.09 Age (years) 0.14 Male (kg) 0.31 Diabetes (%) 0.22 Hx of Hypertension (%) 0.06 Hx of MI (%) 0.08 Hx of Heart Failure (%) 0.55 Cardiogenic Shock* (%) 0.04 Prior PTCA (%) 0.28 Prior CABG (%) * during first 24h post randomization NEJM 2001; 341:1895-1903

  33. ADMIRAL - Place/Time of Administration Place of Study Rx Admin. Time to Study Rx 100 350 p = 0.002 p = 0.02 300 266 80 73 238 250 60 178 200 Time between symptom onset and study drug (min) % of Patients 150 40 26 100 20 50 n = 78 n = 222 0 0 MICU A&E ITU/ Cath Lab MICU/ A&E ITU/ Cath Lab NEJM 2001; 341:1895-1903

  34. ADMIRAL - Angiographic Analysis TIMI 3 Flow Prior To PCI TIMI 3 Flow Post PCI 95.9 95.1 94.3 100 92.6 Placebo 86.7 82.8 Abciximab 80 60 % of Patients p = 0.006 40 p = 0.01 p = 0.04 p = 0.33 p = 0.04 25.8 16.8 20 10.8 5.4 0 Immediately Post-PCI 24 hour Post-PCI 6 month Post-PCI TIMI 3 Flow TIMI 2/3 Flow NEJM 2001; 341:1895-1903

  35. 16 12 8 4 0 0 10 20 30 ADMIRAL - 1° Endpoint through 30 days Death, re-MI or Urgent TVR 14.6  59% p = 0.01 % of Patients 6.0 Placebo Abciximab Days NEJM 2001; 341:1895-1903

  36. Abciximab n = 149 Placebo n = 151 6.0 14.6 3.4 6.6 1.3 2.6 1.3 6.6 ADMIRAL – Components of Primary Endpoint p-value 0.01 Composite 0.19 Death 0.42 Reinfarction 0.02 Urgent TVR NEJM 2001; 341:1895-1903

  37. 16 12 8 7.4 4 0 0 50 100 150 200 ADMIRAL - 1° Endpoint through 6 Months Death, re-MI or Urgent TVR 15.9  53% p = 0.02 % of Patients Placebo Abciximab Days NEJM 2001; 341:1895-1903

  38. 30 Day Composite Endpoint Death, MI or Urgent TVR * includes ischaemic stroke  52% p=0.02  53% p=0.04  51% p=0.03  30% p=0.04 RAPPORT Circ 1998; 98: 735, ISAR-2 JACC 2000; 35:915, ADMIRAL Montalescot ESC 99, CADILLAC Stone TCT 2000

  39. Conlusions Abciximab + Primary PTCA is better than Primary PTCA alone Stent is better than Primary PTCA with or without Abciximab Abciximab + Stent is better than stent alone

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