baseline characteristics

Baseline CharacteristicsBaseline Characteristics

UFH/Enoxaparin + GP IIb/IIIa(N=4,603)

Bivalirudin + GP IIb/IIIa

(N=4,604)

Bivalirudin alone

(N=4,612)

Age (median [range], yrs) 63 [23-91] 63 [21-95] 63 [20-92]

Male 70.6% 69.9% 69.3%

Diabetes 28.4% 27.7% 28.1%

- Insulin requiring 8.5% 8.6% 8.8%

Hypertension 66.8% 67.2% 67.1%

Hyperlipidemia 57.2% 57.4% 57.0%

Current smoker 29.0% 29.3% 29.0%

Prior MI 31.6% 30.5% 31.8%

Prior PCI 39.0% 37.8% 39.9%

Prior CABG 18.2% 17.4% 18.1%

Renal insufficiency 5.7% 6.0% 5.7%

Baseline High Risk FeaturesBaseline High Risk Features



(N=4,604)

Bivalirudin alone(N=4,612)

Biomarker or ST 71.3% 70.1% 70.9%

- Biomarker + 58.1% 56.9% 58.5%

- ST-segment 35.2% 35.4% 34.3%

Biomarker + ST 21.9% 22.2% 21.9%

TIMI Risk Score

- Low (0-2) 16.1% 15.4% 15.6%

- Intermediate (3-4) 53.7% 55.5% 54.5%

- High (5-7) 30.3% 29.1% 29.9%

Invasive ManagementInvasive Management



(N=4,604)

Bivalirudin alone

(N=4,612)

Angiography 99.2% 98.8% 98.9%

Adm. to angio (h) 19.7 (7.0-29.3)† 19.5 (7.0-28.2)† 19.8 (7.3-29.0)†

Drug* to angio/interv (h) 5.6 (1.6-22.5)† 5.0 (1.4-21.4)† 5.2 (1.5-22.5)†

Actual procedure

PCI 55.6% 56.7% 56.8%

CABG 11.9% 10.8% 10.6%

Medical therapy 32.4% 32.5% 32.6%

*In patients receiving study antithrombin pre angiography*In patients receiving study antithrombin pre angiography †median (IQR)

Primary Endpoint Measures (ITT)Primary Endpoint Measures (ITT)

11.7%

7.3%5.7% 5.3%

11.8%

7.7%

Net clinicaloutcome

Ischemic composite Major bleeding

30 d

ay e

ven

ts (

%)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin+GPI (N=4604)

UFH/Enoxaparin + GPI vs. Bivalirudin + GPIUFH/Enoxaparin + GPI vs. Bivalirudin + GPI

PNI <0.0001PSup = 0.93

PNI = 0.007PSup = 0.39

PNI =0.0001PSup = 0.38

11.7%11.8% 1.01 (0.90-1.12)<0.001

0.93

0 1 2

Risk ratio±95% CI

Risk ratio±95% CI

Primaryendpoint

Primary Endpoint Measures (ITT)Primary Endpoint Measures (ITT)UFH/Enoxaparin + GPI vs. Bivalirudin + GPIUFH/Enoxaparin + GPI vs. Bivalirudin + GPI

Net clinical outcome

Ischemic composite

Major bleeding

Bivalirudin + IIb/IIIa betterBivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Bival+ IIb/IIIa

UFH/Enox+ IIb/IIIa

RR (95% CI)p value

(non inferior)(superior)

7.3%7.7% 1.07 (0.92-1.23)0.0150.39

5.7%5.3% 0.93 (0.78-1.10)<0.001

0.38

Upp

er b

oun

dary

non

-infe

riorit

y


11.7%

7.3%5.7%

3.0%

10.1%

7.8%

Net clinicaloutcome

Ischemic composite Major bleeding

30 d

ay e

ven

ts (

%)

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

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

PNI <0.0001PSup = 0.015

PNI = 0.011PSup = 0.32

PNI <0.0001PSup <0.0001

0 1 2


Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Risk ratio±95% CI

Risk ratio±95% CI

Primaryendpoint

Bivalalone

UFH/Enox+ IIb/IIIa

RR (95% CI)


Ischemic composite

Major bleeding

Upp

er b

oun

dary

non

-infe

riorit

y

11.7%10.1% 0.86 (0.77-0.97)<0.0010.015

7.3%7.8% 1.08 (0.93-1.24)0.020.32

5.7%3.0% 0.53 (0.43-0.65)<0.001<0.001

p value(non inferior)

(superior)

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

Components of the Ischemic CompositeComponents of the Ischemic Composite

7.3%

1.3%

4.9%

2.3%2.7%2.4%

5.0%

7.7%

1.5% 1.6%

7.8%

5.4%

Ischemiccomposite

Death Myocardialinfarction

Unplannedrevasc forischemia

30 d

ay e

ven

ts (

%)

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

UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

PSup = 0.32 PSup = 0.34 PSup = 0.35 PSup = 0.78

Major Bleeding EndpointsMajor Bleeding Endpoints

11.8%

5.7%

11.1%

5.3%

3.0%

9.1%

All major bleeding Non CABG major bleeding(primary endpoint)

30 d

ay e

ven

ts (

%)

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


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

Major Bleeding (Primary Endpoint)Major Bleeding (Primary Endpoint)


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% 0.07%

• Retroperitoneal 0.5% 0.6% 0.2%

• Access site 2.6% 2.6% 0.8%

- req interv/surgery 0.3% 0.5% 0.2%

- hematoma ≥5 cm 2.2% 2.2% 0.7%

• Hgb ≥3 g/dL with overt source 2.2% 1.8% 1.0%

• Hgb ≥4 g/dL with no overt source 0.8% 0.7% 0.7%

• Blood transfusion 2.7% 2.6% 1.6%

• Reoperation for bleed 0.04% 0.1% 0.1%

Values in yellow = P<0.05Values in yellow = P<0.05

Minor Bleeding (Non CABG)Minor Bleeding (Non CABG)UFH/Enoxaparin

+ GP IIb/IIIa(N=4,603)

Bivalirudin + GP

IIb/IIIa(N=4,604)

Bivalirudin alone(N=4,612)

Any minor bleeding 21.6% 21.7% 12.8%

• Ecchymoses 5.6% 5.9% 3.6%

• Epistaxis 1.4% 1.9% 0.7%

• GI bleeding 2.8% 1.8% 1.1%

• GU bleeding 0.8% 1.1% 0.3%

• Puncture site 14.7% 14.3% 8.2%

• Hemopericardium 0.1% 0.1% 0.0%

• Pulmonary 0.3% 0.5% 0.1%

• Other 2.1% 2.6% 1.1%

Values in yellow = P<0.05Values in yellow = P<0.05

Bleeding Endpoints (Non-CABG)Bleeding Endpoints (Non-CABG)


Bivalirudin + GP

IIb/IIIa(N=4,604)

Bivalirudin

alone(N=4,612)

P1

ValueP2

Value

ACUITY Scale

- Any 23.9% 23.7% 14.2% 0.88 <0.001

- Major 5.7% 5.3% 3.0% 0.38 <0.001

- Minor 21.6% 21.7% 12.8% 0.84 <0.001

TIMI Scale

- Any 6.6% 6.4% 3.9% 0.67 <0.001

- Major 1.8% 1.6% 0.9% 0.42 <0.001

- Minor 6.4% 6.1% 3.7% 0.52 <0.001

Blood transfusion 2.7% 2.6% 1.6% 0.70 <0.001

P1 = Bivalirudin+GPI vs. UFH/Enox+GPI; P2 = Bivalirudin alone vs. UFH/Enox+GPIP1 = Bivalirudin+GPI vs. UFH/Enox+GPI; P2 = Bivalirudin alone vs. UFH/Enox+GPI

0 1 2

Net Clinical Outcome CompositeNet Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone

Men (n=6444)Women (n=2771)

Diabetes (n=2585)No diabetes (n=6630)

CrCl ≥60 (n=6993)CrCl <60 (n=1644)

Age <65 (n=5051)Age ≥65 (n=4164)

Risk ratio±95% CI

Risk ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

7.8%12.9%

US (n=5224)OUS (n=3991)

10.6%9.5%

8.9%16.1%

10.8%9.8%

9.5%11.6%

9.2%14.7%

11.8%11.5%

10.4%16.8%

13.7%10.9%

10.9%13.5%

P Pint

0.86 (0.71-1.03)0.88 (0.75-1.02)

0.90 (0.77-1.05)0.82 (0.68-0.98)

0.86 (0.74-0.99)0.96 (0.77-1.19)

0.79 (0.64-0.97)0.90 (0.78-1.04)

0.87 (0.75-1.00)0.86 (0.70-1.04)

0.090.09

0.160.03

0.030.71

0.020.16

0.050.12

0.89

0.47

0.43

0.28

0.91

RR (95% CI)


0 1 2


Yes (n=3197)No (n=6008)

Low (0-2) (n=1291)Intermed (3-4) (n=4407)

High (5-7) (n=2449)

Elevated (n=5368)Normal (n=3841)

Risk ratio±95% CI

Risk ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

9.2%11.3%

12.2%11.1%

P Pint

0.76 (0.65-0.89)1.02 (0.86-1.21)

12.2%7.1%

13.3%9.4%

0.92 (0.80-1.06)0.75 (0.61-0.93)

0.230.01

<0.0010.83

0.35

0.02

0.18

13.0%8.6%

13.7%10.6%

0.96 (0.80-1.14)0.81 (0.69-0.95)

0.610.01 0.42

Biomarkers (CK/Trop)

ST Deviation

TIMI Risk Score

Pre Thienopyridine

6.4% 10.2% 0.63 (0.43-0.91) 0.019.4% 10.2% 0.92 (0.77-1.10) 0.34

13.9% 15.2% 0.92 (0.76-1.11) 0.36

Yes (n=5192)No (n=4023)

RR (95% CI)


0 1 2



BivalAlone

UFH/Enox+ IIb/IIIa

P Pint

0.59

11.6% 13.3% 0.87 (0.75-1.00) 0.09

10.6% 18.2% 0.97 (0.75-1.26) 0.84

5.1% 6.5% 0.78 (0.58-1.04) 0.09

0.62

8.3% 9.8% 0.85 (0.67-1.06) 0.15

9.2% 9.4% 0.98 (0.78-1.23) 0.86

12.5% 14.4% 0.87 (0.73-1.05) 0.14

0.56

9.1% 10.0% 0.91 (0.73-1.12) 0.36

6.7% 7.1% 0.94 (0.80-1.10) 0.46

10.6% 12.6% 0.84 (0.65-1.10) 0.21

RR (95% CI)

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

No prior AT (n=3290)

Consistent Rx (n=5519)

Crossover (n=3211)

A-thrombin crossover

Early (<3.0 h)

Intermediate (3.0-19.7 h)

Late (≥19.7 h)

Risk ratio±95% CI

Risk ratio±95% CI

Actual treatment

Rand. to angio/interv.tertiles

Net Clinical Outcome Composite EndpointNet Clinical Outcome Composite 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%


Ischemic Composite EndpointIschemic Composite Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)





Bivalirudin alone (N=4612) 0.307.8%


Major Bleeding EndpointMajor Bleeding Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)





Bivalirudin alone (N=4612) <0.00013.0%


UFH/Enox +UFH/Enox + GP IIb/IIIaGP IIb/IIIa

Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa

BivalirudinBivalirudinalonealone

Predicted RateRate RateRate PowerPower RateRate PowerPower

Endpoint NINI SupSup NINI SupSup

Net clinical outcome 12.4%12.4% 10.3%10.3% 99%99% 88%88% 10.5%10.5% 99%99% 81%81%

Ischemic events 6.5%6.5% 5.3%5.3% 99%99% 67%67% 6.5%6.5% 87%87% --

Major bleeding 9.0%9.0% 7.5%7.5% 99%99% 73%73% 6.0%6.0% 99%99% 99%99%

NI = non-inferiority; Sup = superiority

Event Rates and Power CalculationsEvent Rates and Power Calculations


Summary Conclusions: Primary ResultsSummary Conclusions: Primary Results

Endpoint


Ischemic events

Major bleeding






Observed RateRate

Endpoint

Net clinical outcome 11.7%11.7%

Ischemic events 7.3%7.3%

Major bleeding 5.7%5.7%








Observed RateRate RateRate PPValueValueEndpoint

Net clinical outcome 11.7%11.7% 11.8%11.8% <0.001 NI<0.001 NI

Ischemic events 7.3%7.3% 7.7%7.7% 0.007 NI0.007 NI

Major bleeding 5.7%5.7% 5.3%5.3% 0.001 NI0.001 NI





Conclusions: Primary ResultsConclusions: Primary Results




Observed RateRate RateRate PPValueValue

RateRate PPValueValueEndpoint

Net clinical outcome 11.7%11.7% 11.8%11.8% <0.001 NI<0.001 NI 10.1%10.1% 0.015 Sup0.015 Sup

Ischemic events 7.3%7.3% 7.7%7.7% 0.007 NI0.007 NI 7.8%7.8% 0.011 NI0.011 NI

Major bleeding 5.7%5.7% 5.3%5.3% 0.001 NI0.001 NI 3.0%3.0% <0.001 Sup<0.001 Sup


Clinical ImplicationsClinical Implications

In patients with moderate-high risk ACS undergoing an early invasive strategy with use of GP IIb/IIIa inhibitors

Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin

However, compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition

A bivalirudin alone strategy results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days

In patients with moderate-high risk ACS undergoing an early invasive strategy with use of GP IIb/IIIa inhibitors

Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin

However, compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition

A bivalirudin alone strategy results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days

baseline characteristics

Documents