gregg w. stone md for the acuity investigators

Gregg W. Stone MD

for the ACUITY Investigators

Gregg W. Stone MD

for the ACUITY Investigators

A Prospective, Randomized Trial of Bivalirudin in Acute Coronary Syndromes

Final One-Year Results from the ACUITY Trial

A Prospective, Randomized Trial of Bivalirudin in Acute Coronary Syndromes

Final One-Year Results from the ACUITY Trial

Moderateand highrisk ACS

(n=13,819)

Study Design – First RandomizationStudy Design – First Randomization

An

gio

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ith

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice



UFH/Enox+ GP IIb/IIIa(n=4,603)

Bivalirudin+ GP IIb/IIIa(n=4,604)

BivalirudinAlone

(n=4,612)

R*

*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Medicalmanagement

PCI

CABG

56%

11%

33%

Study Design – Second RandomizationStudy Design – Second Randomization

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

Bivalirudin+ GP IIb/IIIa(N=4,604)

BivalirudinAlone

(N=4,612)

R*

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy

GPI upstream (N=2294)

GPI CCL for PCI (N=2309)

GPI upstream (N=2311)

GPI CCL for PCI (N=2293)





*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderateand highrisk ACS(n=13,819

3 Primary Endpoints (at 30 Days)3 Primary Endpoints (at 30 Days)

1. Composite net clinical benefit =1. Composite net clinical benefit =2. Ischemic composite2. Ischemic composite

3. Major bleeding3. Major bleedingoror

Death from any cause Myocardial infarction

- During medical Rx: Any biomarker elevation >ULN

- Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves

- Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves

Unplanned revascularization for ischemia

3 Primary Endpoints (at 30 Days)3 Primary Endpoints (at 30 Days)

1. Composite net clinical benefit =1. Composite net clinical benefit =

2. Ischemic composite2. Ischemic composite

3. Major bleeding3. Major bleedingoror

Non CABG related bleeding- Intracranial bleeding or intraocular bleeding- Intracranial bleeding or intraocular bleeding

-- Retroperitoneal bleedingRetroperitoneal bleeding-Access site bleed requiring intervention/surgeryAccess site bleed requiring intervention/surgery

- Hematoma ≥5 cmHematoma ≥5 cm-- Hgb Hgb ≥3g/dL with an overt source or ≥3g/dL with an overt source or ≥4g/dL w/o overt source≥4g/dL w/o overt source

-- Blood product transfusionBlood product transfusion Reoperation for bleeding

Baseline CharacteristicsBaseline CharacteristicsUFH/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%

Weight (median [IQR], kg) 83 [73-95] 83 [73-95] 84 [73-96]

Diabetes 28.5% 27.8% 28.1%

- Insulin requiring 8.5% 8.7% 8.9%

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 38.9% 37.8% 39.9%

Prior CABG 18.2% 17.4% 18.1%

Renal insufficiency* 19.2% 19.2% 18.9%

* creatinine clearance <60 mL/min

Baseline High Risk FeaturesBaseline High Risk FeaturesUFH/Enoxaparin

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


(N=4,604)

Bivalirudin alone(N=4,612)

Biomarker or ST 73.1% 71.6% 72.4%

- Biomarker + 59.4% 58.6% 60.3%

- Troponin + 58.3% 57.2% 59.2%

- ST-segment 35.2% 35.4% 34.3%

TIMI Risk Score†

- 0-2* 16.1% 15.4% 15.6%

- 3-4 53.7% 55.5% 54.5%

- 5-7 30.3% 29.1% 29.9%

*80.1% were biomarker+ or had baseline STΔ

†97% were TIMI intermediate or high risk, or biomarker+, or +STΔ

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) – 30 DaysPrimary Endpoint Measures (ITT) – 30 DaysUFH/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

0.38Up

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Stone GW et al. NEJM 2006;355:2203-16Stone GW et al. NEJM 2006;355:2203-16

0 1 2

Primary Endpoint Measures (ITT) – 30 DaysPrimary Endpoint Measures (ITT) – 30 Days

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)

Net clinical outcome

Ischemic composite

Major bleeding

Up

per

bo

un

dar

y n

on

-in

feri

ori

ty

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

7.3%7.8% 1.08 (0.93-1.24)0.010.32

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

Stone GW et al. NEJM 2006;355:2203-16Stone GW et al. NEJM 2006;355:2203-16

Medication Compliance: Anti-platelet agentsMedication Compliance: Anti-platelet agents

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


(N=4,604)

Bivalirudin alone(N=4,612)

Aspirin use

- Before angio/PCI 98.0% 97.8% 97.9%

- Hospital discharge 94.5% 95.1% 94.6%

- 30 day follow-up* 92.6% 92.8% 93.1%

- 1 year follow-up* 87.6% 88.3% 88.1%

Thienopyridine use

- Before angio/PCI 62.8% 64.7% 64.2%

- Hospital discharge 71.6% 72.7% 73.0%

- 30 day follow-up* 66.7% 68.7% 68.7%

- 1 year follow-up* 44.8% 44.3% 44.1%

*Greater than 50% of days since last visit

Patient Follow-up at 1-Year*Patient Follow-up at 1-Year*

Heparin + IIb/IIIa4,603

Bivalirudin + IIb/IIIa4,604

Bivalirudin alone4,612

All patientsN = 13,819

25 Withdrawn62 Lost to follow-up

Heparin + IIb/IIIa4,516 (98.1%)

1-year FU

Bivalirudin + IIb/IIIa4,502 (97.8%)

1-year FU

Bivalirudin alone4,521 (98.0%)

1-year FU



R

*Endpoints adjudicated: Composite ischemia(death, MI, unplanned revasc) and stent thrombosis

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

25

Co

mp

osi

te i

sch

emia

(%

)

Days from Randomization

10

20 UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

30 day

7.4%0.367.8%0.347.9%

—

EstimateP

(log rank)

16.3%0.3816.5%0.3116.4%

1 year

—

p=0.55

Bivalirudin alone vs. Hep+GPIHR [95% CI] = 1.05 (0.95-1.17)

Bivalirudin+GPI vs. Hep+GPIHR [95% CI] = 1.05 (0.94-1.16)

Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)

Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)

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

Co

mp

osi

te i

sch

emia

(%

)


0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

25

10

20 Routine upstream IIb/IIIaDeferred selective IIb/IIIa

EstimateP

(log rank)

30 day

7.1%0.10

8.1%

EstimateP

(log rank)

15.7%17.2%

1 year

Ischemic Composite Endpoint – GPIIb/IIIa Inhibitor Timing Randomization


0.15

Routine Upstream GPI vs. Deferred Selective GPI Routine Upstream GPI vs. Deferred Selective GPI

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

25

Co

mp

osi

te i

sch

emia

(%

)


10

20 Routine upstream IIb/IIIaDeferred selective IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

30 day

7.1% 0.18

8.1% 0.59

7.9% —

EstimateP

(log rank)

15.7% 0.20

17.2% 0.88

16.4%

1 year

— p=0.30



GPI Strategies vs. Bivalirudin Alone GPI Strategies vs. Bivalirudin Alone

0 1 2

Composite Ischemia at 1-yearComposite Ischemia at 1-year

Hazard ratio±95% CI


Bivalalone

UFH/Enox+ IIb/IIIa

HR (95% CI) Pint

0.67


19.8% 19.2% 1.09 (0.96-1.23)

21.1% 20.7% 1.04 (0.79-1.36)

9.0% 9.6% 0.97 (0.76-1.24)

Actual Treatment

PCI (n=5179)

CABG (n=1040)

Medical (n=2994)

17.7%

14.6%

16.4%

16.1%

1.14 (0.99-1.30)

0.95 (0.80-1.14)0.11

Biomarkers (CK/Trop)

Elevated (n=5072)

Normal (n=3402)

16.2%

16.4%

17.2%

14.3%

0.97 (0.86-1.11)

1.20 (1.01-1.44)0.07

Pre Thienopyridine

Yes (n=5751)

No (n=3305)

UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin aloneUFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone1 yr KM estimate

Stent Thrombosis (Protocol): Definite/Probable Stent Thrombosis (Protocol): Definite/Probable

UFH/Enoxaparin + GP IIb/IIIa

(N=2348)

Bivalirudin + GP

IIb/IIIa(N=2403)

Bivalirudin

alone(N=2407)

P1

ValueP2

Value

Total-all stent pts 2.3% 2.4% 1.9% 0.38 0.74

0 – 30 days 1.3% 1.6% 1.3% 0.39 0.97

30 days – 1 year 1.0% 0.8% 0.5% 0.78 0.52

Total – at least one DES implanted

2.5% 2.4% 1.8% 0.44 0.89

• 0 – 30 days 1.2% 1.6% 1.2% 0.28 0.87

• 30 days – 1 year 1.3% 0.7% 0.6% 0.82 0.64

Total – only BMS implanted

2.3% 2.6% 2.0% 0.69 0.71

• 0 – 30 days 1.6% 1.6% 1.5% >0.99 0.87

• 30 days – 1 year 0.6% 1.0% 0.5% 0.49 0.65

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 30 60 90 120 150 180 210 240 270 300 330 360 3900

4

5

Mo

rtal

ity

(%)


2

1

Mortality: 524 total deaths at 1-yearMortality: 524 total deaths at 1-yearUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

1.4%0.531.6%0.391.6%

—

EstimateP

(log rank)

4.4%0.934.2%0.663.8%

1 year

—

p=0.90

Bivalirudin+GPI vs. Hep+GPIHR [95% CI] = 0.99 (0.80-1.22)

30 day

3

Bivalirudin alone vs. Hep+GPIHR [95% CI] = 0.95 (0.77-1.18)

Early and Late MortalityLandmark analysis

Early and Late MortalityLandmark analysis

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

2

1

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

30 dayEstimate

P(log rank)

1.4%0.531.6%0.391.6%

—

EstimateP

(log rank)

3.1%0.542.7%0.212.3%

30d - 1 year

—

p=0.45

Mo

rtal

ity

(%)


Early and Late Mortality – PCI SubgroupLandmark analysis

Early and Late Mortality – PCI SubgroupLandmark analysis

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

2

1

UFH/Enoxaparin + IIb/IIIa (N=2560)Bivalirudin + IIb/IIIa (N=2606)

Bivalirudin alone (N=2619)

EstimateP

(log rank)

30 day

0.9%0.451.2%0.631.1%

—

EstimateP

(log rank)

3.1%0.912.4%0.752.2%

1 year

—

p=0.78

Mo

rtal

ity

(%)


0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

5

Mo

rtal

ity

(%)


2

1

Mortality – GPIIb/IIIa Inhibitor Timing Randomization


Routine Upstream GPI vs. Deferred Selective GPI Routine Upstream GPI vs. Deferred Selective GPI

EstimateP

(log rank)

30 dayEstimate

P(log rank)

Routine upstream IIb/IIIaDeferred selective IIb/IIIa

1.4%0.34

1.6%4.3%4.3%

1 year

0.66

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

5

2

1Estimate

P(log rank)

30 dayEstimate

P(log rank)

Routine upstream IIb/IIIaDeferred selective IIb/IIIa

1.4%1.6%

4.3%4.3%

1 year

Bivalirudin alone 1.6% — 3.8% —

0.300.93

0.870.54

p=0.82



GPI Strategies vs. Bivalirudin AloneGPI Strategies vs. Bivalirudin Alone

Mo

rtal

ity

(%)


0 1 2

Death at 1-yearDeath at 1-yearUFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin aloneUFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone



Bivalalone

UFH/Enox+ IIb/IIIa

HR (95% CI) Pint

0.96


3.2% 4.0% 0.95 (0.70-1.29)

6.8% 6.7% 1.03 (0.64-1.66)

4.0% 4.3% 0.95 (0.66-1.37)

Actual Treatment

PCI (n=5179)

CABG (n=1040)

Medical (n=2994)

4.8%

2.4%

5.0%

3.6%

1.04 (0.80-1.34)

0.84 (0.55-1.28)0.40

Biomarkers (CK/Trop)

Elevated (n=5072)

Normal (n=3402)

3.5%

4.0%

4.2%

4.4%

0.90 (0.68-1.18)

1.05 (0.74-1.48)0.52

Pre Thienopyridine

Yes (n=5751)

No (n=3305)

1 yr KM estimate

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

Mo

rtal

ity

(%)


2

1

UFH/Enoxaparin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

3.9%

0.273.1%

1 year

—

REPLACE-2 + ACUITY-PCI: MortalityREPLACE-2 + ACUITY-PCI: MortalityUFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

Mo

rtal

ity

(%)


2

1

REPLACE-2 + ACUITY-PCI: MortalityREPLACE-2 + ACUITY-PCI: MortalityUFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

UFH/Enoxaparin + IIb/IIIa (n=5568)Bivalirudin alone (n=5613)

EstimateP

(log rank)

0.7%0.790.6%

30 day

—

EstimateP

(log rank)

3.0%0.242.0%

30d - 1 year

—

Mo

rtal

ity

(%)


0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

25

10

20Estimate

Patients with MI (N=705) 11.4%

1 year

Patients with Major Bleed (N=645) 14.9%

Patients w/o Major Bleed (N=13,168) 3.6%Patients w/o MI (N=13,108) 3.8%

Pts with vs. without MI and Major Bleeding within 30dPts with vs. without MI and Major Bleeding within 30d

Impact of Major Adverse Events Within 30 Days on Subsequent Mortality

Impact of Major Adverse Events Within 30 Days on Subsequent Mortality

Mo

rtal

ity

(%)


0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

30

10

25

20

p=0.04

1 yearEstimate

Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)

3.4%No MI or Major Bleed (N=12,557)MI only (without Major Bleed) (N=611) 8.6%

Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year

Cox model adjusted for baseline predictors, with non-CABG major bleeding and MI as time-updated covariates

Cox model adjusted for baseline predictors, with non-CABG major bleeding and MI as time-updated covariates

Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year

Major bleedingMajor bleeding 2.89 (2.24-3.72)2.89 (2.24-3.72) <0.0001<0.0001

Myocardial InfarctionMyocardial Infarction 2.47 (1.87-3.27)2.47 (1.87-3.27) <0.0001<0.0001

0 1 2 3 4

HR ± 95% CIHR ± 95% CI P-valueP-valueHR (95% CI)HR (95% CI)

Day 0 – 2 after MIDay 0 – 2 after MI 12.6 (7.8-20.4)12.6 (7.8-20.4) 29 (37.6)29 (37.6) <0.0001<0.0001

Day 3 – 7 after MIDay 3 – 7 after MI 5.3 (2.7-10.4)5.3 (2.7-10.4) 11 (14.3)11 (14.3) <0.0001<0.0001

Day 8 – 35 after MIDay 8 – 35 after MI 1.6 (0.8-3.1)1.6 (0.8-3.1) 12 (15.6)12 (15.6) 0.180.18

Day > 35 after MIDay > 35 after MI 1.2(0.8-1.9)1.2(0.8-1.9) 25 (32.5)25 (32.5) 0.340.34

Day 0 – 2 after Major BleedDay 0 – 2 after Major Bleed 3.0 (1.6-5.6)3.0 (1.6-5.6) 12 (12.9)12 (12.9) 0.00090.0009

Day 3 – 7 after Major BleedDay 3 – 7 after Major Bleed 4.0 (2.1-7.5)4.0 (2.1-7.5) 15 (16.1)15 (16.1) <0.0001<0.0001

Day 8 – 35 after Major BleedDay 8 – 35 after Major Bleed 4.5 (2.8-7.4)4.5 (2.8-7.4) 25 (26.9)25 (26.9) <0.0001<0.0001

Day > 35 after Major BleedDay > 35 after Major Bleed 2.2 (1.5-3.2)2.2 (1.5-3.2) 41 (44.1)41 (44.1) <0.0001<0.0001

P-value

Influence of Non-CABG Major Bleeding and MI in the First 30 Days on the Risk of Death Over 1 YearInfluence of Non-CABG Major Bleeding and MI in

the First 30 Days on the Risk of Death Over 1 Year

Deaths (n/%)HR ± 95% CI

0.5 1 2 4 8 16

HR (CI)

ConclusionsConclusions

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

Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin

Compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition

A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1-year

The results of this study further establish the important relationship between iatrogenic bleeding complications and the long-term prognosis in patients with ACS

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

Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin

Compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition

A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1-year

The results of this study further establish the important relationship between iatrogenic bleeding complications and the long-term prognosis in patients with ACS

gregg w. stone md for the acuity investigators

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