1. Major Bleeding is Associated with Increased Short-Term Mortality and Ischemic Complications in Non-ST Elevation Acute Coronary Syndromes: The ACUITY Trial Steven V. Manoukian1, Michele D. Voeltz1, Frederick Feit2, Ramin Ebrahimi3,Roxana Mehran4, Eugenia Nikolsky4, Jeffrey W. Moses4, A. Michael Lincoff5, Spencer B. King, III6, Gregg W. Stone4 1Emory University School of Medicine, Atlanta, GA 2New York University School of Medicine, New York, NY 3University of California Los Angeles, Los Angeles, CA 4Columbia University Medical Center, New York, NY 5The Cleveland Clinic, Cleveland, OH 6Fuqua Heart Center, Atlanta, GA

2. Presenter Disclosure Information
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Steven V. Manoukian, MD, FACC The Medicines Co.
Research Support (modest)
Consultant (modest)
Speaker (modest)
sanofi aventis/BMS

3. Background: The ACUITY Trial (N=13819) Major Bleeding in ACS and PCI
Major bleeding is a significant complication of non-ST elevation acute coronary syndromes (NSTE-ACS) and percutaneous coronary intervention (PCI).
Recent data suggest that major bleeding is associated with an increase in adverse outcomes in ACS and PCI, including mortality.
We evaluated the impact of major bleeding on short-term mortality and ischemic events in patients with moderate and high-risk NSTE-ACS undergoing an invasive strategy.
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

4. Background: OASIS Registry, OASIS-2, and CURE Major Bleeding is Associated with Increased Mortality in ACS
Eikelboom JW et al. Circulation 2006;114:

5. Background: The REPLACE-2 Trial (N=6010) Major Bleeding is Increased with Abciximab and Eptifibatide vs. Bivalirudin in PCI
Major Bleeding
2.5% vs. 4.0%, p=0.0251
Major Bleeding
2.2% vs. 4.1%, p=0.0021
4.0%
4.1%
2.5%
2.2%
Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-737.

6. Pre-procedural Anemia 30-Day Revascularization
Background: The REPLACE-2 Trial (N=6010) Predictors of One-Year Mortality in PCI
Variable
OR (95%CI)
p-value
Age ≥ 75
2.28 (1.51, 3.46)
0.0001
Pre-procedural Anemia
2.12 (1.49, 3.13)
0.0002
BMI > 25 (vs )
0.61 (0.40, 0.99)
0.007
Pre-procedure LVEF ≤ 50%
2.15 (1.44, 3.21)
CHF
3.58 (2.27, 5.65)
<.0001
Prior Angina
2.16 (1.25, 3.75)
0.006
Major Bleeding
2.66 (1.44, 4.92)
0.002
30-Day MI
2.46 (1.44, 4.20)
0.001
30-Day Revascularization
3.30 (1.36, 8.00)
0.008
Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion
Voeltz MD, Patel AD, Feit F, et al. Am J Cardiol, in press.

7. Methods: The ACUITY Trial (N=13819) Study Design and Definitions
The ACUITY Trial was a randomized comparison of:
(1) bivalirudin alone (BIV),
(2) heparin or enoxaparin + glycoprotein inhibition (H+GPI),
(3) BIV + glycoprotein inhibition (BIV+GPI),
in moderate and high-risk NSTE-ACS.
Major bleeding (non-CABG-related) was defined as: intracranial, intraocular, or retroperitoneal; access site bleed with intervention; hematoma >5cm; Hgb drop >3g/dL with source or >4g/dL without source; or transfusion.
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

8. Methods: The ACUITY Trial (N=13819) First Randomization
Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy
UFH or
Enoxaparin
+ GP IIb/IIIa
Bivalirudin
Alone R*
Angiography within 72h
Medical
management
PCI
CABG
Moderate-
high risk
ACS
Aspirin in all
Clopidogrel
dosing and timing
per local practice
*Stratified by pre-angiography thienopyridine use or administration
Stone GW et al. AHJ 2004;148:764–75.

9. Methods: The ACUITY Trial (N=13819) Second Randomization
Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy
Bivalirudin
Alone
UFH or Enoxaparin
Routine upstream GPI in all pts
GPI started in CCL for PCI only R
Medical
management
PCI
CABG
Moderate-
high risk
ACS
Angiography within 72h
Aspirin in all
Clopidogrel
dosing and timing
per local practice
Stone GW et al. AHJ 2004;148:764–75.

10. Days from Randomization
Methods: The ACUITY Trial (N=13819) Overall Net Clinical Outcome Composite Endpoint 15
UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 10
Cumulative Events (%)
Estimate P
(log rank)
11.7%
UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604)
0.89
11.8%
Bivalirudin alone (N=4612)
0.014
10.1% 5 5 10 15 20 25 30 35
Days from Randomization
ACUITY Trial. Stone GW. ACC 2006.

11. Methods: The ACUITY Trial (N=13819) Overall Bleeding Endpoints
PSup=0.31
PSup<.001
PSup=0.38
PSup<0.0001
Stone GW. ACC 2006.

12. Methods: The ACUITY Trial (N=13819) Overall Primary Endpoint Measures for Upstream vs. Deferred IIb/IIIa
PNI <0.0001
PSup = 0.93
PNI = 0.044
PSup = 0.13
PNI <
PSup = 0.009
Stone GW. ACC 2006.

13. 644 (4.7%) of 13819 patients had major bleeding.
Results: The ACUITY Trial (N=13819) Major Bleeding (Non-CABG Related) in ACS
644 (4.7%) of patients had major bleeding.
Patients with major bleeding were (p<0.05):
older, more likely to be female, of lower body weight, and have diabetes, hypertension, and impaired creatinine clearance,
more likely to present with elevated cardiac biomarkers or as high-risk (ST-changes or elevated biomarkers),
less likely to use tobacco and have prior PCI.
Major bleeding was less frequent in patients treated with:
Bivalirudin vs. Heparin(s) + GPI (3.0% vs. 5.7%, p<0.0001),
Bivalirudin vs. Bivalirudin + GPI (3.0% vs. 5.3%, p<0.0001).
Major bleeding was associated with higher 30-day mortality and ischemic event rates.
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

14. Major Bleeding (N=644, 4.7%) No Major Bleeding (N=13,175, 95.3%)
Results: The ACUITY Trial (N=13819) Major Bleeding and Baseline Characteristics
Major Bleeding
(N=644, 4.7%)
No Major Bleeding
(N=13,175, 95.3%)
P-value
Age (median [range], yrs)
69 [37-95]
62 [20-93]
<0.0001
Female
49.4%
29.1%
Weight (median [IQR], kg)
79.5 [68-92]
84 [73-95]
Diabetes
34.5%
27.8%
0.0002
Hypertension
73.3%
66.7%
0.0005
CrCl ≥ 60 ml/min
62.7%
81.8%
Current smoker
24.7%
29.3%
0.0126
Prior PCI
29.0%
37.8%
High risk (ST / biomarkers)
82.0%
71.8%
CK-MB / Troponin +
68.1%
59%
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

15. Results: The ACUITY Trial (N=13819) Major Bleeding (Non-CABG Related)
UFH/Enoxaparin + GP IIb/IIIa
(N=4,603)
Bivalirudin GP IIb/IIIa
(N=4,604)
Bivalirudin alone
(N=4,612)
Any major bleeding
5.7%
5.3%
3.0%
Intracranial
0.07%
0.04%
Retroperitoneal
0.5%
0.6%
0.2%
Access site
2.5%
0.8%
- req interv/surgery
0.3%
- hematoma ≥5 cm
2.2%
0.7%
Hgb  ≥3 g/dL with overt source
1.8%
1.0%
Hgb  ≥4 g/dL with no overt source
Blood transfusion
2.7%
2.6%
1.6%
Reoperation for bleed
0.1%
Stone GW. ACC 2006.
Values in yellow = P<0.05

16. Results: The ACUITY Trial (N=13819) Major Bleeding, Ischemic Endpoints, and Mortality
P< for all
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

17. Results: The ACUITY Trial (N=13819) Major Bleeding and Myocardial Infarction
P< for all
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

18. (D/MI/unplanned revasc) 23.1% 6.8%
Results: The ACUITY Trial (N=13819) Major Bleeding, Ischemic Endpoints, and Mortality
Major Bleeding
(N=644, 4.7%)
No Major Bleeding
(N=13175, 95.3%)
P-value
Death
7.3%
1.2%
<0.0001
Composite ischemia
(D/MI/unplanned revasc)
23.1%
6.8%
Death/MI
19.4%
5.6% MI
14.6%
4.6%
Non-Q wave
10.6%
3.8%
Q wave
4.2%
0.9%
Unplanned revascularization
7.6%
2.2%
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

19. Results: The ACUITY Trial (N=13819) Predictors of Major Bleeding
Risk ratio ± 95% CI
RR (95% CI)
P-value
Age >75 (vs )
Anemia
CrCl <60mL/min
Diabetes
Female gender
High-risk (ST / biomarkers)
Hypertension
No prior PCI
Heparin(s) + GPI (vs. Bivalirudin)
1.51 ( )
<0.0001
1.88 ( )
1.54 ( )
1.21 ( )
0.052
1.90 ( )
1.67 ( )
1.23 ( )
0.0476
1.36 ( )
0.0028
2.04 ( )
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

20. Results: The ACUITY Trial PCI Population (N=7789) Major Bleeding, Ischemic Endpoints, and Mortality in the PCI Population
P< for all
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

21. High-risk (ST / biomarkers) Hypertension No prior PCI
Results: The ACUITY Trial PCI Population (N=7789) Predictors of Major Bleeding in the PCI Population
Risk ratio ± 95% CI
RR (95% CI)
P-value
Age >75 (vs )
Anemia
CrCl <60mL/min
Diabetes
Female gender
High-risk (ST / biomarkers)
Hypertension
No prior PCI
Prior antithrombotic therapy
Heparin(s) + GPI (vs. Bivalirudin)
1.56 ( )
0.0009
1.89 ( )
<0.0001
1.68 ( )
1.30 ( )
0.0248
2.08 ( )
1.42 ( )
0.0178
1.33 ( )
0.0287
1.47 ( )
0.0019
1.23 ( )
0.0768
2.08 ( )
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

22. Results: The ACUITY Trial (N=13819) Predictors of Mortality at 30 Days
Predictors of Mortality at 30 Days in The ACUITY Trial
Variable OR
95% CI
p-value
Age > 75 years
2.55
<0.0001
LVEF < 50%
2.96
Prior CVA
1.94
0.024
ECG Changes
2.32
Elevated Cardiac Markers
1.97
0.005
MI (within 30 days)
3.96
Major Bleeding
7.55
PCI (vs. CABG)
0.29
Manoukian SV, Feit F, Mehran R, et al. Unpublished.

23. An increased risk of major bleeding is associated with:
Conclusion: The ACUITY Trial (N=13819) Major Bleeding in Patients with ACS
Major bleeding is associated with increased short-term mortality and ischemic event rates.
Bivalirudin results in lower rates of major bleeding compared to GPI-based strategies.
An increased risk of major bleeding is associated with:
baseline factors: age, female gender, chronic kidney disease, anemia, hypertension, no prior PCI;
presentation factors: high-risk presentation;
treatment factors: treatment with heparin(s) + GPI.
Knowledge of these findings is important in the assessment of the hemorrhagic risk of, and decision-making for each patient.
Prevention of major bleeding is essential in order to minimize rates of short-term mortality and ischemic events in NSTE-ACS.
Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.