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Background: Major Bleeding in ACS and PCI Major bleeding is a significant complication of acute coronary syndromes (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 mortality and ischemic events in patients with ACS undergoing PCI from the ACUITY Trial. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
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Major Bleeding is Associated with Increased 30-Day Mortality and
Ischemic Complications in Patients with Non-ST Elevation Acute Coronary
Syndromes UndergoingPercutaneous Coronary Intervention:
The ACUITY Trial Steven V. Manoukian1, Michele D. Voeltz1, Frederick Feit2, Roxana Mehran3, Eugenia
Nikolsky3, George D. Dangas3, Ramin Ebrahimi4, A. Michael Lincoff5, Spencer B. King, III6, Gregg W. Stone3
1Emory University School of Medicine, Atlanta, GA2New York University School of Medicine, New York, NY
3Columbia University Medical Center, New York, NY4University of California Los Angeles, Los Angeles, CA
5The Cleveland Clinic, Cleveland, OH6Fuqua Heart Center, Atlanta, GA
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 SupportConsultantSpeaker
sanofi aventis/BMSConsultant
Relevant Conflict of Interest Statement
Background:
Major Bleeding in ACS and PCI• Major bleeding is a significant complication of
acute coronary syndromes (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 mortality and ischemic events in patients with ACS undergoing PCI from the ACUITY Trial.
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Background: The REPLACE-2 Trial
Major Bleeding is Increased with Abciximab and Eptifibatide vs. Bivalirudin in PCI
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
3.5%
4.0%
Bivalirudin Abciximab0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
3.5%
4.0%
Bivalirudin Eptifibatide
Major Bleeding2.5% vs. 4.0%, p=0.0251
Major Bleeding2.2% vs. 4.1%, p=0.0021
4.0%
2.5%2.2%
4.1%
Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-737.
0.4%
13.0%
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
14.0%
Major Bleeding
Background: The REPLACE-2 Trial
Major Bleeding is Associated withIncreased Mortality in
Elderly Patients Undergoing PCI
= Yes= No
p<0.0001
30-D
ay M
orta
lity
806 patients (13.4%) classified as elderly, >75 years of age.
Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613.
Background: The REPLACE-2 Trial
Predictors of One-Year Mortality in PCIRisk Factor Odds Ratio 95% CI p-value
Treatment Group (BIV vs. H+GPI) 0.77 0.516 to 1.149 0.201Age > 75 2.069 1.273 to 3.362 0.0033
Congestive Heart Failure 2.991 1.777 to 5.032 <0.0001Pre-procedure LV function <35% 2.827 1.565 to 5.106 0.0006
Diabetes Mellitus 1.987 1.311 to 30.12 0.0012Prior Angina 1.948 1.115 to 3.403 0.0191
Baseline Creatinine Clearance 1.008 1.000 to 1.015 0.0455Major Bleeding 2.767 1.444 to 5.302 0.0022
30 Day Revascularization 3.075 1.244 to 7.597 0.01530 Day MI 2.503 1.428 to 4.386 0.0014
IABP 3.598 1.233 to 10.499 0.0191
Feit F, Voeltz MD, Attubato MA, Lincoff AM, Chew D, Bittl JA, Wolski K, Topol EJ, Manoukian SV. Manuscript.
Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion.
5.13.0
5.37.0
18.616.1 15.3
22.8
0.0
10.0
20.0
30.0
40.0
No BleedBleed
Moscucci M et al. Eur Heart J 2003;24:1815-23.Moscucci M et al. Eur Heart J 2003;24:1815-23.
P<0.001
Overall Unstable NSTEMI STEMIOverall Unstable NSTEMI STEMI ACS AnginaACS Angina
Mor
talit
y (%
)Background: The GRACE Registry
Major Bleeding is Associated with Increased Mortality in ACS
Background: OASIS Registry, OASIS-2, and CURE
Major Bleeding is Associated with Increased Mortality in ACS
Eikelboom JW et al. Circulation 2006;114:774-782.Eikelboom JW et al. Circulation 2006;114:774-782.
Methods: The ACUITY Trial
Study Design and Definitions• The ACUITY Trial compared: heparin or
enoxaparin + glycoprotein inhibition (H+GPI), bivalirudin + glycoprotein inhibition (BIV+GPI), and bivalirudin monotherapy (BIV) in 13819 patients with moderate and high-risk NSTE-ACS.
• Major bleeding (non-CABG-related) was defined as: intracranial, intraocular, or retroperitoneal, access site with intervention, hematoma >5cm, Hgb drop >3g/dL with source or >4g/dL without source, transfusion.
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Moderate-high risk
ACS
Methods: The ACUITY Trial (N=13819)
First Randomization
Ang
iogr
aphy
with
in 7
2h
Aspirin in allClopidogrel
dosing and timingper local practice
UFH orEnoxaparin+ GP IIb/IIIa
Bivalirudin+ GP IIb/IIIa
BivalirudinAlone
R*
*Stratified by pre-angiography thienopyridine use or administration
Stone GW et al. AHJ 2004;148:764–75.
Medicalmanagement
PCI
CABG
Moderate and high-risk unstable angina or NSTEMI undergoing an Moderate and high-risk unstable angina or NSTEMI undergoing an invasive strategyinvasive strategy
Methods: The ACUITY Trial (N=13819)
Overall Net Clinical OutcomeComposite Endpoint
0
5
10
15
0 5 10 15 20 25 30 35
Cum
ulat
ive
Even
ts (%
)
Days from Randomization
Estimate P(log rank)
11.7%UFH/Enoxaparin + IIb/IIIa (N=4603)Bivalirudin + IIb/IIIa (N=4604) 0.8911.8%
Bivalirudin alone (N=4612) 0.01410.1%
UFH/Enoxaparin + GPIUFH/Enoxaparin + GPI vs. vs. Bivalirudin + GPIBivalirudin + GPI vs. vs. Bivalirudin AloneBivalirudin Alone
ACUITY Trial. Stone GW. ACC 2006.
PSup = 0.32 PSup = 0.34 PSup = 0.35 PSup = 0.78
7.3%
1.3%
4.9%
2.3% 2.7% 2.4%
5.0%
7.7%
1.5% 1.6%
7.8%
5.4%
Ischem iccomposite
Death Myocardialinfarction
Unplannedrevasc forischem ia
30 d
ay e
vent
s (%
)
UFH/Enox+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)
Methods: The ACUITY Trial (N=13819)
Overall Ischemic Endpoints
Stone GW. ACC 2006.
Methods: The ACUITY Trial (N=13819)
Overall Bleeding Endpoints
11.8%
5.7%
11.1%
5.3%3.0%
9.1%
All Major Bleeding Non-CABG Major Bleeding(prim ary endpoint)
30 d
ay e
vent
s (%
)
Heparin+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)
PSup=0.38 PSup<0.0001PSup=0.31 PSup<.001
Stone GW. ACC 2006.
Moderate-high risk
ACS
Methods: The ACUITY Trial (N=13819)
Second Randomization
Ang
iogr
aphy
with
in 7
2h
Aspirin in allClopidogrel
dosing and timingper local practice
Medicalmanagement
PCI
CABGBivalirudin
Alone
UFH or EnoxaparinRoutine upstream
GPI in all ptsGPI started in
CCL for PCI onlyR
Bivalirudin
RRoutine upstream
GPI in all ptsGPI started in
CCL for PCI only
Stone GW et al. AHJ 2004;148:764–75.
Moderate and high-risk unstable angina or NSTEMI undergoing an Moderate and high-risk unstable angina or NSTEMI undergoing an invasive strategyinvasive strategy
Methods: The ACUITY Trial (N=13819)
Overall Primary Endpoint Measures for Upstream vs. Deferred IIb/IIIa
11.7%
7.1% 6.1%4.9%
11.7%
7.9%
Net clinicaloutcom e
Ischemiccom posite
Major bleeding
30 d
ay e
vent
s (%
)
Routine Upstream IIb/IIIa (N=4605) Deferred PCI IIb/IIIa (n=4602)
PNI <0.0001PSup = 0.93
PNI = 0.044PSup = 0.13
PNI < 0.0001PSup = 0.009
Stone GW. ACC 2006.
Results: The ACUITY Trial PCI Population (N=7789)
Major Bleeding (Non-CABG Related) in ACS Patients Undergoing PCI
• 462 (5.9%) of 7789 patients had major bleeding by 30 days.• Patients with major bleeding were (p<0.05):
– older, female, and had lower body weight, diabetes, hypertension, impaired creatinine clearance, high-risk (ST-changes or elevated biomarkers), and elevated biomarkers.
– less likely to have prior PCI.– more likely to receive a glycoprotein inhibitor, have PCI duration >1h,
sheath dwell time >6h.• Major bleeding was less frequent for:
– Bivalirudin vs. Heparin(s) + GPI (3.5% vs. 6.8%, p<0.0001),– Bivalirudin vs. Bivalirudin + GPI (3.5% vs. 7.5%, p<0.0001).
• Major bleeding was associated with higher 30-day mortality and ischemic event rates.
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Results: The ACUITY Trial PCI Population (N=7789)
Major Bleeding and Baseline CharacteristicsMajor Bleeding(N=462, 5.9%)
No Major Bleeding(N=7327, 94.1%) P-value
Age (median [range], yrs) 69 [37-95] 62 [21-92] <0.0001Female 48.3% 25.5% <0.0001Weight (median [IQR], kg) 78.3 [68-93] 84 [74-96] <0.0001Diabetes 35.2% 27.1% 0.0002Hypertension 73.8% 65.5% 0.0001Current smoker 27.4% 31.1% 0.0929Prior PCI 30.3% 39.2% 0.0002CrCl ≥ 60 ml/min 62.3% 82.8% <0.0001High-risk (ST / biomarkers) 83.0% 75.9% 0.0007CK-MB / Troponin+ 70.0% 64.7% 0.0271Any GPI use 83.8% 68.0% <0.0001Sheath removal time >6h 24.4% 15.7% <0.0001PCI duration >1h 20% 10.5% <0.0001
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Results: The ACUITY Trial PCI Population (N=7789)
Major Bleeding by Treatment Strategy
6.8%7.5%
3.5%
Non-CABG Major Bleeding (primary endpoint)
Heparin+GPI Bivalirudin+GPI Bivalirudin alone
P<0.0001
P<0.0001
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Results: The ACUITY Trial PCI Population (N=7789)
Major Bleeding, Ischemic Endpoints, and Mortality
9.3%
3.0%
17.1%
5.4%
24.2%
5.5%7.8%
0.8%
IschemicComposite
Death MI (all) UnplannedRevasc
30 d
ay e
vent
s (%
)
Major Bleeding (N=462, 5.9%) No Major Bleeding (N=7327, 94.1%)
P<0.0001 for all
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Results: The ACUITY Trial PCI Population (N=7789)
Major Bleeding and Myocardial Infarction
4.8%
12.6%
17.1%
0.8%
5.5% 4.8%
MI (all) Non-Q MI Q-MI
30 d
ay e
vent
s (%
)
Major Bleeding (N=462, 5.9%) No Major Bleeding (N=7327, 94.1%)
P<0.0001 for all
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Results: The ACUITY Trial PCI Population (N=7789)
Major Bleeding, Ischemic Endpoints, and Mortality
Major Bleeding(N=462, 5.9%)
No Major Bleeding(N=7327, 94.1%) P-value
Death 5.4% 0.8% <0.0001 Composite ischemia (D/MI/unplanned
revasc)24.2% 7.8% <0.0001
Death/MI 20.1% 6.1% <0.0001MI 17.1% 5.5% <0.0001
• Non-Q wave 12.6% 4.8% <0.0001• Q wave 4.8% 0.8% <0.0001
Unplanned revascularization 9.3% 3.0% <0.0001
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
0 1 2 3
P-valueRR (95% CI)Risk ratio ± 95% CI
Results: The ACUITY Trial PCI Population
Predictors of Major Bleeding
Age >75 (vs. 55-75)
AnemiaCrCl <60mL/min
DiabetesFemale gender
High-risk (ST / biomarkers)Hypertension
Prior PCIPrior antithrombotic therapy
Heparin(s) + GPI (vs. Bivalirudin)
1.56 (1.19-2.04) 0.00091.89 (1.48-2.41) <0.00011.68 (1.29-2.18) <0.00011.30 (1.03-1.63) 0.02482.08 (1.68-2.57) <0.00011.42 (1.06-1.90) 0.01781.33 (1.03-1.70) 0.02871.47 (1.15-1.88) 0.00191.23 (0.98-1.55) 0.07682.08 (1.56-2.76) <0.0001
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Conclusion: The ACUITY Trial PCI Population (N=7789)
Major Bleeding in Patients with ACS Undergoing PCI
• Major bleeding is associated with increased 30-day mortality and ischemic event rates in patients with ACS undergoing PCI.
• Bivalirudin results in lower rates of major bleeding compared to GPI-based strategies.
• Factors associated with an increase in the risk of major bleeding:– age, female gender, diabetes, hypertension, chronic kidney disease, prior
PCI, anemia;– high-risk presentation;– treatment with heparin(s) + GPI (and trend for prior AT therapy).
• Knowledge of these factors is important in the assessment of the hemorrhagic risk of, and decision-making for an individual patient.
• Prevention of major bleeding in this setting is essential to improve outcomes.
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
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