major bleeding is associated with increased 30-day mortality and ischemic complications in patients...

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


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.


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.


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


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)


Overall Ischemic Endpoints

Stone GW. ACC 2006.


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


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


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.



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



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



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



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



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


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


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.


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