Erasmus MC, Thoraxcenter The Additive Value of Tirofiban Administered With the High-Dose Bolus in the Prevention of Ischemic Complications During High-Risk Coronary Angioplasty The ADVANCE Trial M. Valgimigli University of Ferrara Italy Erasmus MC, Thoraxcenter The Netherlands Department of Cardiology University of Ferrara

30-day composite events (death, MI, urgent TVR) by clinical status Tirofiban p = 0.032 9,0 8,5 5,8 acs pts p = 0.002 Abciximab 8,0 7,59 7,0 5,6 4,5 non acs pts p = 0.32 6,01 6,0 5,0 4,0 3,0 2,0 1,0 0,0 all pts

Dr Schneider’s Hypothesis Baseline platelet reactivity is not uniform in patients undergoing PCI The higher the baseline value, the worse the outcome Baseline platelet reactivity is proportional to the clinical status, lower in elective pts, higher in NSTEACS and highest in STEMI pts Tirofiban, at Restore regimen, is just enough, soon after the bolus, to control platelet reactivity in elective patients Circ 01; 104: 18; AJC 02; 90: 1421; AJC 03; 91: 334; AJC 03; 91: 872; Frossard Circ 04; 110

AIM To re-assess the efficacy of Tirofiban when given at SHDB on top of ADP receptor blockers in: Elective patients NSTE-ACS patients

AIM To re-assess the efficacy of Tirofiban when given at SHDB on top of ADP receptor blockers in High-Risk: Elective patients Multivessel treatment Diabetes NSTE-ACS patients High-risk features (ESC guidelines)

PCI Indications Silent Ischemia ACS Viability SA

NSTE-ACS Population (n=111) 79% 73% Troponin positive 55% ST >0.5 mm 2 leads 23% Diabetes

Study Protocol 160-325mg ASA 500mg ticlidopine bolus + 250mg bid or 300mg clopidogrel bolus + 75mg daily 100U/kg bolus UFH + Bolus to maintain 300s ACT 50-70U/kg bolus UFH + Bolus to maintain 200s ACT Treatment regimens are outlined above. As is typical in placebo controlled trials, the dose of UFH is higher in the placebo arm, compared to the GP IIb/IIIa arm. Placebo 25mcg/kg bolus tirofiban + 0.15mcg/kg/min infusion for 24-48 hours Valgimigli et al. (2004) JACC 44:14-19

Endpoints Primary Endpoint Secondary Endpoints Death, nonfatal MI, TVR and thrombotic bailout GP IIb/IIIa Secondary Endpoints Each component of the primary endpoint Effect of drug on troponin I levels Effects in prespecified subgroups Diabetics Patients with ACS TIMI major and minor bleeding ≈199 Patients 30% events Controls 40% events reduction β-error 0.8 α-error .05 The primary endpoint was a quad endpoint, taking into consideration the standard MACE (death, MI and uTVR) and including the incidence of additional GP IIb/IIIa therapy as bailout for a thrombotic event/complication during PCI. This allowed clinicians to utilize a GP IIb/IIIA inhibitor in those placebo patients that were not receiving maximal anti-platelet therapy. Secondary analysis looked at the individual components of the primary endpoint (including traditional MACE), effects of drug on reducing increased events of troponin I/CK-MB leaks and analyzing pre-specified subgroups (diabetics and patients with ACS/NSTEMI). TIMI major and minor bleeding was analyzed for safety profile. Valgimigli et al. (2004) JACC 44:14-19

Baseline Characteristics Placebo (n=101) HDB Tirofiban P-Value Age (yr) 687 699 NS Male sex (%) 66 69 Diabetes (%) 45 53 15 19 Previous PCI (%) 50 Pervious MI (%) 21 Creatinine (mg/dl) 1.10.3 1.00.2 Heart failure (%) Valgimigli et al. (2004) JACC 44:14-19

Baseline Characteristics Placebo (n=101) HDB Tirofiban P-Value Age (yr) 687 699 NS Male sex (%) 66 69 Diabetes (%) 45 53 15 19 Previous PCI (%) 50 Pervious MI (%) 21 Creatinine (mg/dl) 1.10.3 1.00.2 Heart failure (%) Valgimigli et al. (2004) JACC 44:14-19

Baseline Characteristics Placebo (n=101) HDB Tirofiban P-Value Age (yr) 687 699 NS Male sex (%) 66 69 Diabetes (%) 45 53 15 19 Previous PCI (%) 50 Pervious MI (%) 21 Creatinine (mg/dl) 1.10.3 1.00.2 Heart failure (%) Valgimigli et al. (2004) JACC 44:14-19

Baseline Characteristics Placebo (n=101) HDB Tirofiban P-Value Age (yr) 687 699 NS Male sex (%) 66 69 Diabetes (%) 45 53 15 19 Previous PCI (%) 50 Pervious MI (%) 21 Creatinine (mg/dl) 1.10.3 1.00.2 Heart failure (%) Valgimigli et al. (2004) JACC 44:14-19

Baseline Characteristics Placebo (n=101) HDB Tirofiban P-Value Age (yr) 687 699 NS Male sex (%) 66 69 Diabetes (%) 45 53 15 19 Previous PCI (%) 50 Pervious MI (%) 21 Creatinine (mg/dl) 1.10.3 1.00.2 Heart failure (%) Valgimigli et al. (2004) JACC 44:14-19

Baseline Characteristics Placebo (n=101) HDB Tirofiban P-Value Age (yr) 687 699 NS Male sex (%) 66 69 Diabetes (%) 45 53 15 19 Previous PCI (%) 50 Pervious MI (%) 21 Creatinine (mg/dl) 1.10.3 1.00.2 Heart failure (%) Valgimigli et al. (2004) JACC 44:14-19

Baseline Characteristics Placebo (n=101) HDB Tirofiban P-Value Age (yr) 687 699 NS Male sex (%) 66 69 Diabetes (%) 45 53 15 19 Previous PCI (%) 50 Pervious MI (%) 21 Creatinine (mg/dl) 1.10.3 1.00.2 Heart failure (%) Valgimigli et al. (2004) JACC 44:14-19

Baseline Characteristics Placebo (n=101) HDB Tirofiban P-Value Age (yr) 687 699 NS Male sex (%) 66 69 Diabetes (%) 45 53 15 19 Previous PCI (%) 50 Pervious MI (%) 21 Creatinine (mg/dl) 1.10.3 1.00.2 Heart failure (%) Valgimigli et al. (2004) JACC 44:14-19

1° End-point Days Suirvival Probability % P=0,01 100 90 20% 80 70 35% 60 Suirvival Probability % Tirofiban SHDB Placebo 50 40 30 20 10 50 100 150 200 250 300 350 400 Days Valgimigli et al. (2004) JACC 44:14-19

Clinical Outcome % 0.01 0.048 n.s. 0.052 n.s. 1°Endpoint MACE Death MI TVR Valgimigli et al. (2004) JACC 44:14-19

Troponin I and CK-MB P<0. 01 P=0.001 ng/ml Troponin I CK-MB HDB tirofiban significantly decreased the number of patients with increased troponin I and CK-MB concentrations normally associated with heart muscle damage. Troponin I CK-MB Valgimigli et al. (2004) JACC 44:14-19

Subgroup Analysis 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Tirofiban Better Acute Coronary Syndrome Yes No Diabetes Yes Subgroup analysis reveals a significant benefit for diabetic and ACS patients treated with HDB tirofiban versus placebo—once again showing the benefit of this drug in the particularly high risk patients. No 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Tirofiban Better Placebo Better Valgimigli et al. (2004) JACC 44:14-19

Safety Results No incidence of major bleeding No RBC transfusions No severe thrombocytopenia One mild thrombocytopenia in each group Placebo 20 Tirofiban 18 16 14 P=0.19 12 # Patients 10 8 There is a slight, but not significant increase in minor bleeding in patients treated with HDB of tirofiban. Moreover, there were no incidences of major bleeding, red blood cell transfusions, or severe thrombocytopenia. There was one incidence of mild thrombocytopenia in each arm. 6 4 2 Minor Bleeding Valgimigli et al. (2004) JACC 44:14-19

CONCLUSIONS As safe as More effective than Tirofiban when given at SHDB, immediately before high-risk PCIs, to patients who have been pre-treated with thienopyridines was: As safe as More effective than UFH alone in the prevention of periprocedural ischemic complications Our current findings, based on a limited and selected sample size, should be viewed as preliminary, thus giving input for further research in this field. Valgimigli et al. (2004) JACC 44:14-19