1. 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

2. 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

3. 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

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

5. 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)

6. PCI Indications
Silent Ischemia
ACS
Viability SA

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

8. 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 hours
Valgimigli et al. (2004) JACC 44:14-19

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

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

20. 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

21. 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

22. 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

23. 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