relevant conflict of interest statement

Transfusion is Associated with Increased 30-Day Mortality and

Ischemic Complications in Non-ST Elevation Acute Coronary Syndromes:

The ACUITY Trial

Steven V. Manoukian1, Michele D. Voeltz1, Frederick Feit2, Roxana Mehran3, George D. Dangas3, Eugenia Nikolsky3, A. Michael Lincoff4, Spencer B. King5, III, E. Magnus Ohman6,

Gregg W. Stone3

1Emory University School of Medicine, Atlanta, GA2New York University School of Medicine, New York, NY

3Columbia University Medical Center, New York, NY4The Cleveland Clinic, Cleveland, OH

5Fuqua Heart Center, Atlanta, GA6Duke University Medical Center, Durham, NC

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

Consultant

Speaker

sanofi aventis/BMSConsultant

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

Consultant

Speaker

sanofi aventis/BMSConsultant

Relevant Conflict of Interest Statement

Background:

Transfusion in ACS and PCI

• Blood product transfusion is an important complication in acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) patients treated with potent antithrombotic and antiplatelet agents.

• Recent data suggest that transfusion is associated with an increase in adverse outcomes in ACS and PCI, including mortality.

• We assessed the impact of transfusion on mortality and ischemic events in patients with ACS from the ACUITY Trial.

Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

1.7%

5.0%

2.7%

6.7%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

Transfusions Major Bleeding

Background: The REPLACE-2 Trial

Transfusion and Major Bleeding areMore Frequent in Elderly Patients

Undergoing PCI

= Elderly, >75

= Not Elderly, <75

806 patients (13.4%) classified as elderly, >75 years of age.

p<0.0001 p=0.0001

Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613.


Transfusion and Mortality in PCI

Non-transfused Transfused

1.9%1.0%

0.2%

10.6%

6.3%

13.9%

0.0%2.0%4.0%6.0%8.0%

10.0%12.0%14.0%16.0%

30 DayMortality*

6 MonthMortality*

1 YearMortality*

*p<0.0001

Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005.

0.5%

15.0%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

Transfusions


Transfusion is Associated withIncreased Mortality in

Elderly Patients Undergoing PCI

= Yes

= No

p<0.0001 p=0.0001

30-D

ay M

ort

alit

y

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.

30 Day Survival By Transfusion Group

0.9

0.92

0.94

0.96

0.98

1

0 5 10 15 20 25 30 35

Days

Su

rviv

al

Ra

tes

No Transfusion

Transfusion

Rao SV et al. JAMA 2004;292:1555-1562.

Background: GUSTO IIb, PURSUIT, PARAGON B

Transfusion and 30-Day Mortality in ACS

(N=24111)

Background: GUSTO IIb, PURSUIT, PARAGON B

Transfusion and 30-Day Mortality in ACS

*Transfusion as a time-dependent covariate*Transfusion as a time-dependent covariate

1.01.0 1010-4.0-4.0

Adjusted for transfusion Adjusted for transfusion propensitypropensity

Adjusted for baselineAdjusted for baselinecharacteristicscharacteristics

Adjusted for baseline Adjusted for baseline Characteristics, bleedingCharacteristics, bleedingpropensity, transfusion propensity, transfusion Propensity, & nadir HCTPropensity, & nadir HCT

3.77 (3.14, 4.52)3.77 (3.14, 4.52)

3.54 (2.96, 4.23)3.54 (2.96, 4.23)

3.94 (3.26, 4.75)3.94 (3.26, 4.75)

(N=24111)

Rao SV et al. JAMA 2004;292:1555-1562.

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.

• We evaluated outcomes in patients who received transfusion (non-CABG-related) within 30 days of randomization.


Moderate-high risk

ACS

Methods: The ACUITY Trial (N=13819)

First Randomization

An

gio

gra

ph

y w

ith

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

ACUITY Design. 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

Cu

mu

lati

ve E

ven

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 AloneUFH/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 iccom posite

Death Myocardialinfarction

Unplannedrevasc forischem ia

30

da

y e

ve

nts

(%

)

UFH/Enox+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)


Overall Ischemic Endpoints



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

da

y e

ve

nts

(%

)

Heparin+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)

PSup=0.38 PSup<0.0001PSup=0.31 PSup<.001


Moderate-high risk

ACS


Second Randomization

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice

Medicalmanagement

PCI

CABG

BivalirudinAlone

UFH or EnoxaparinRoutine upstream

GPI in all ptsGPI started in

CCL for PCI only

R

Bivalirudin

R

Routine 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 clinicaloutcome

Ischemiccomposite

Major bleeding

30

da

y e

ve

nts

(%

)

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


Results: The ACUITY Trial (N=13819)

Transfusion (non-CABG-related) in ACS

• 319 (2.3%) of 13819 patients had transfusion by 30 days.• Patients with transfusion were (p<0.05):

– older, female, non-smokers, and had lower body weight, diabetes, hypertension, impaired creatinine clearance, elevated biomarkers, and high-risk (ST-changes or elevated biomarkers).

– more likely to receive pre-treatment with a thienopyridine.– more likely to have a >4h randomization to angiography time.

• Transfusion was less frequent for:– Bivalirudin vs. Heparin(s) + GPI (1.6% vs. 2.7%, p<0.0001),– Bivalirudin vs. Bivalirudin + GPI (1.6% vs. 2.6%, p<0.0001).

• Transfusion was associated with higher 30-day mortality and ischemic event rates.



Transfusion and Baseline Characteristics

Transfusion(N=319, 2.3%)

No Transfusion(N=13500, 97.7%)

P-value

Age (median [range], yrs) 72 [38-95] 63 [20-93] <0.0001

Female 56.1% 29.5% <0.0001

Weight (median [IQR], kg) 76 [66-90] 84 [73-95] <0.0001

Diabetes 43.8% 27.7% <0.0001

Hypertension 80.9% 66.7% <0.0001

Current smoker 21.5% 29.3% 0.0027

Prior CABG 22% 17.8% 0.0527

CrCl ≥ 60 ml/min 51% 81.6% <0.0001

Prior thienopyridine 69.3% 63.8% 0.0478

High-risk (ST / biomarkers) 79.5% 72.1% 0.0041

CK-MB / Troponin+ 65.2% 59.3% 0.0382

Random Angiogram >4h 60.8% 53.7% 0.0117



Transfusion by Treatment Strategy

2.7% 2.6%

1.6%

Transfusion

Heparin + GPI Bivalirudin + GPI Bivalirudin alone


P<0.001

P=ns


Transfusion, Ischemic Endpoints, and Mortality

9.4%

2.3%

18.8%

11.0%

29.2%

4.8%7.1%

1.3%

IschemicComposite

Death MI (all) UnplannedRevasc

30 d

ay e

ven

ts (

%)

Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%)

P<0.0001 for all



Transfusion and Myocardial Infarction

5.3%

13.8%

18.8%

0.9%

4.8% 3.8%

MI (all) Non-Q MI Q-MI

30

da

y ev

ents

(%

)

Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%)

P<0.0001 for all



Transfusion, Ischemic Endpoints, and Mortality

Transfusion(N=319, 2.3%)

No Transfusion(N=13500, 97.7%) P-value

Death 11.0% 1.3% <0.0001

Composite ischemia (D/MI/unplanned

revasc)29.2% 7.1% <0.0001

Death/MI 26.0% 5.8% <0.0001

MI 18.8% 4.8% <0.0001

• Non-Q wave 13.8% 3.8% <0.0001

• Q wave 5.3% 0.9% <0.0001

Unplanned revascularization 9.4% 2.3% <0.0001


0 1 2 3 4 5

P-valueRR (95% CI)

Age >75 (vs. 55-75)

Anemia

CrCl <60mL/min

Diabetes

Female gender

High-risk (ST / biomarkers)

Hypertension

Heparin(s) + GPI (vs. Bivalirudin)

1.420 (1.055-1.910) 0.0060

3.764 (2.919-4.855) <0.0001

2.097 (1.568-2.803) <0.0001

1.560 (1.209-2.014) 0.0060

2.233 (1.739-2.867) <0.0001

1.754 (1.297-2.372) 0.0003

1.457 (1.051-2.020) 0.0241

1.728 (1.256-2.379) 0.0007

Results: The ACUITY Trial

Predictors of Transfusion

Risk ratio ± 95% CIRisk ratio ± 95% CI


Conclusion: The ACUITY Trial (N=13819)

Transfusion in Patients with ACS• Transfusion is associated with increased 30-day mortality and ischemic

event rates in patients with ACS undergoing an invasive strategy.• Bivalirudin results in lower transfusion rates compared to GPI-based

strategies.• Factors associated with an increase in the risk of transfusion:

– age, female gender, diabetes, hypertension, chronic kidney disease, anemia;

– high-risk presentation;– treatment with heparin(s) + GPI.

• Knowledge of these factors is important in the assessment of the transfusion risk of, and decision-making for an individual patient.

• Minimizing transfusion risk is paramount in order to optimize outcomes in this setting.


relevant conflict of interest statement

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