1. Impact of clopidogrel loading dose on the safety and effectiveness of bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction: The HORIZONS AMI trial
George Dangas, Giulio Guagliumi, Bernhard Witzenbichler, Deepak Bhatt, Frederick Feit, Magnus Ohman, S. Chiu Wong, Helen Parise, Roxana Mehran, Gregg W. Stone
Dangas et al, SCAI-ACCi2 2008

2. Background
In the HORIZONS AMI trial, in pts undergoing primary PCI. bivalirudin monotherapy (Biv) compared to UFH plus GP IIb/IIIa inhibitors resulted in:
– Reduced 30 day rates of major bleeding,
– Comparable composite major adverse cardiovascular events (MACE)
– Enhanced freedom from net adverse clinical events (NACE).
All pts were to receive a clopidogrel loading dose in the ER, either 300 mg or 600 mg, and randomization was stratified by this decision.
Whether the beneficial effects of bivalirudin are independent of the clopidogrel loading dose has not been reported.
Dangas et al, SCAI-ACCi2 2008

3. Baseline Characteristics
300mg LD
600mg LD
P value
Age
60.5 [52.9, 70.5]
60.1 [52.2, 69.3]
0.14
Male
75.5%
76.9%
0.39
Diabetes
17.6%
15.6%
0.13
Insulin
3.7%
4.5%
0.27
Hypertension
51.9%
52.7%
0.63
Hyperlipidemia
41.5%
42.4%
0.62
Current smoking
43.4%
47.4%
0.03
Anemia
9.4%
10.7%
0.25
Platelet ct (x103 cells/mm3)
250.5 [210, 299]
245.0 [207, 287]
0.02
Renal insufficiency
2.9%
3.1%
0.86
Prior MI
9.6%
9.8%
0.89
Prior PCI
8.5%
Prior CABG
2.3%
0.26
History of PVD
3.9%
0.46
History of CHF
US stratification
30.6%
16.8%
<.0001
Dangas et al, SCAI-ACCi2 2008

4. Baseline Characteristics
300mg LD
600mg LD
P value
Weight (kg)
80.0
[71.0, 90.0]
[71.0, 90.7]
0.17
BMI (kg/m2)
27.1
[24.6, 30.1]
27.0
[24.5, 30.3]
0.50
Chest pain to ER (hours)
2.2
[1.3, 4.0]
[1.3, 3.8]
0.45
KILLIP Class 2-4
11.5%
6.9%
<.0001
LVEF <40%
15.1%
13.7%
0.28
Femoral a. access
87.3%
96.7%
Radial a. access
12.4%
2.9%
Venous access
10.1%
8.0%
0.03
Closure Device
20.3%
33.2%
Peak ACT (sec)
299 [244, 379]
316 [254, 392]
IABP
6.5%
4.8%
0.0353
Dangas et al, SCAI-ACCi2 2008

5. Drug Administration 300mg LD 600mg LD P- value HEPARIN
Pre-Randomization Heparin
60.7%
68.7%
<.0001
Pre-Procedure Heparin
67.9%
72.9%
0.002
Heparin in cath lab, as anticoagulant
51.4%
50.0%
0.43
BIVALIRUDIN
Bivalirudin in cath lab, as anticoagulant
48.4%
0.38
GP IIb/IIIa
In the ER
3.2%
7.5%
In the cath lab, before sheath insertion
11.5%
12.3%
0.50
In the cath lab, Any
52.0%
50.5%
0.42
ANY
55.2%
54.1%
0.54
Dangas et al, SCAI-ACCi2 2008

6. Procedural characteristics (PCI)
300mg LD
600mg LD
P- value
Treated vessels
LAD
41.9%
40.3%
0.38
LCX
15.5%
15.8%
0.80
RCA
40.6%
42.6%
0.28 LM
0.7%
0.5%
0.41
SVG
1.2%
0.8%
0.24
LIMA/ RIMA
0.1%
0.0%
0.35
Door to Balloon (hours)
1.8 [1.3, 2.3]
1.6 [1.2, 2.2]
<.0001
One or more stents implanted
95.6%
96.3%
0.31
Multiple vessels treated
4.5%
4.1%
0.68
Multiple lesions treated
9.9%
11.3%
0.26
Dangas et al, SCAI-ACCi2 2008

7. Procedural characteristics (PCI)
300mg LD
600mg LD
P- value
TIMI flow pre PCI
TIMI 0/1
65.6%
65.2%
0.83
TIMI 2
15.5%
16.2%
0.58
TIMI 3
19.0%
18.6%
0.80
Final TIMI flow after PCI
2.5%
1.8%
0.16
5.0%
6.8%
0.048
92.5%
91.5%
0.31
Dangas et al, SCAI-ACCi2 2008

8. Overall: Primary Outcomes (ITT)
*NACE = MACE or major bleeding
**Not related to CABG
***MACE = All cause death, reinfarction, ischemic TVR or stroke
Dangas et al, SCAI-ACCi2 2008

9. Primary Outcomes (ITT)
The impact of Biv was independent of the dose of clopidogrel loading. Interaction P values for the above 3 endpoints = (NACE) 0.41 (Major bleeding), and 0.75 (MACE).
300 mg LD
600 mg LD
P=0.15
P=0.01
P=0.56
P=0.01
P=0.002
P=0.71
Dangas et al, SCAI-ACCi2 2008

10. Overall: 30 Day MACE Components*
300 mg LD
600 mg LD
P-value
Death
3.1%
1.9%
0.03
- Cardiac
2.7%
0.11
- Non cardiac
0.4%
0.1%
0.054
Reinfarction
2.4%
1.3%
0.02
- Q-wave
1.5%
1.1%
0.37
- Non Q-wave
1.0%
0.3%
Ischemic TVR
2.8%
2.0%
0.15
- Ischemic TLR
2.6%
1.8%
0.13
- Ischemic remote TVR
0.76
Stroke
0.058
*CEC adjudicated
Dangas et al, SCAI-ACCi2 2008

11. Bivalirudin group: 30 Day MACE Components*
300 mg LD
600 mg LD
P-value
Death
2.6%
1.4%
0.06
- Cardiac
2.1%
1.3%
0.19
- Non cardiac
0.5%
0.1%
0.11
Reinfarction
2.8%
0.02
- Q-wave
1.8%
1.1%
0.26
- Non Q-wave
0.2%
Ischemic TVR
3.3%
2.3%
0.20
- Ischemic TLR
0.13
- Ischemic remote TVR
0.0%
1.00
Stroke
0.9%
0.6%
0.56
*CEC adjudicated
Dangas et al, SCAI-ACCi2 2008

12. Overall: 30 Day Stent Thrombosis
300 mg LD
600 mg LD
P-value
ARC definite or probable*
2.8%
1.7%
0.04
- definite
2.1%
1.3%
0.11
- probable
0.7%
0.4%
0.20
- acute (≤24 hrs)
1.00
- subacute (>24 hrs – 30d)
2.2%
1.0%
0.008
*Protocol definition of stent thrombosis, CEC adjudicated
Dangas et al, SCAI-ACCi2 2008

13. BIV group: 30 Day Stent Thrombosis
300 mg LD
600 mg LD
P-value
ARC definite or probable*
3.5%
1.7%
0.03
- definite
3.1%
1.5%
0.04
- probable
0.4%
0.2%
0.61
- acute (≤24 hrs)
1.6%
0.9%
0.26
- subacute (>24 hrs – 30d)
2.1%
0.8%
*Protocol definition of stent thrombosis, CEC adjudicated
Dangas et al, SCAI-ACCi2 2008

14. Overall: 30 Day Bleeding Endpoints
300 mg LD
600 mg LD
P-Value
Protocol Major, non CABG
8.7%
5.8%
0.002
Protocol Major, All
11.0%
7.2%
0.0002
Protocol Minor
13.9%
11.2%
0.02
Blood transfusion
3.6%
2.4%
0.057
TIMI Major
4.3%
3.4%
0.19
TIMI Minor
5.6%
2.5%
<0.0001
TIMI Major or Minor
10.0%
6.2%
GUSTO LT* or Severe
0.6%
0.4%
0.33
GUSTO Moderate
4.9%
3.2%
GUSTO LT or Sev or Mod
5.4%
*Life threatening
Dangas et al, SCAI-ACCi2 2008

15. Prediction of 30-day Outcomes
Multivariate predictors using logistic regression model
Hazard Ratio
95% CI p
Death (78 events)
KILLIP class 1
0.3
<0.001
Ccr
0.97
History of PVD
2.01
0.035
Clopidogrel 600mg LD
0.76
0.232
Age -
Death/Reinfarction (127 events)
0.33
Platelet count
1.002
0.029
1.02
1-1.05
0.042
0.7
0.056
Diabetes
History of CHF
US stratification
Dangas et al, SCAI-ACCi2 2008

16. Prediction of 30-day Outcomes
Multivariate Predictors Using Cox proportional hazards model
Hazard Ratio
95% CI p
MACE (172 events)
KILLIP class 1
0.41
<0.001
Clopidogrel 600mg LD
0.72
0.036
Platelet count
1.002
0.026
Age
1.03
US stratification
1.49
0.019
History of PVD
1.87
0.016
History of CHF -
Major bleeding (226 events)
Bivalirudin
0.57
0.63
0.01
Creatinine clearance
0.99
0.002
Female
1.45
Anemia
1.62
0.008
2.44
IABP
3.53
Closure device
0.80
0.17
0.89
0.39
Dangas et al, SCAI-ACCi2 2008

17. Conclusions In patients with STEMI undergoing primary PCI:
600 mg loading dose of clopidogrel was associated with significantly lower 30- day mortality, reinfarction and stent thrombosis rates compared with 300 mg loading dose.
600 mg loading dose of clopidogrel did not increase the risk of bleeding compared with 300 mg loading dose.
Biv monotherapy significantly reduces major bleeding and NACE, independently of the clopidogrel loading dose.
By multivariate analysis, 600 mg loading dose of clopidogrel was an independent predictor of lower 30-day MACE (compared with 300 mg LD, Odds Ratio=0.72), but was not independently associated with death, reinfarction or major bleeding.
Dangas et al, SCAI-ACCi2 2008