Dr. Harvey White on behalf of the ACUITY investigators

ACUITY PCIA Prospective Trial of Patients with ACS

Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs. Bivalirudin With or Without GP IIb/IIIa Inhibitors

ACUITY PCIA Prospective Trial of Patients with ACS

Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs. Bivalirudin With or Without GP IIb/IIIa Inhibitors

Dr. Harvey White on behalf of the ACUITY

investigators

Dr. Harvey White on behalf of the ACUITY

investigators

DisclosureDisclosure

Harvey D. White

Research Grants: Alexion, Fournier Laboratories, Sanofi

Aventis, Johnson & Johnson, Eli Lilly, Proctor & Gamble, Merck Sharpe & Dohme, Schering Plough, Roche, The Medicines Company, Glaxo Smith Kline, Pfizer, Neuren Pharmaceuticals, NIH

Consultant: Sanofi Aventis, The Medicines Company

Harvey D. White

Research Grants: Alexion, Fournier Laboratories, Sanofi

Aventis, Johnson & Johnson, Eli Lilly, Proctor & Gamble, Merck Sharpe & Dohme, Schering Plough, Roche, The Medicines Company, Glaxo Smith Kline, Pfizer, Neuren Pharmaceuticals, NIH

Consultant: Sanofi Aventis, The Medicines Company

Moderateand highrisk ACS

(n=13,819)

Study Design – First RandomizationStudy Design – First Randomization

An

gio

gra

ph

y w

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

Study Design – Second RandomizationStudy Design – Second Randomization

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

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

GP IIb/IIIa upstream (N=2294)

GP IIb/IIIa CCL for PCI (N=2309)

GP IIb/IIIa upstream (N=2311)

GP IIb/IIIa 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)





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

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

BivalirudinAlone

(n=4,612)

R*

Composite Ischemia: 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

ACUITY Primary EndpointsACUITY Primary Endpoints

Non-CABG Major Bleeding Intracranial bleeding or intraocular bleeding Retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma ≥5 cm Hgb ≥ 3 g/dL with , or ≥ 4 g/dL without overt source Blood product transfusion Reoperation for bleeding

Net Clinical Outcome (Composite Ischemia, Non-CABG Major Bleeding)

ACUITY: Primary results – 30 daysACUITY: Primary results – 30 daysUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin AloneUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

7.3%5.7%

11.7%

7.7%

11.8%

5.3%

3.0%

10.1%

7.8%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

UFH/Enox+ GP IIb/IIIa (N=4603) Bivalirudin+GP IIb/IIIa (N=4604) Bivalirudin alone (N=4612)

PNI <0.001PSup = 0.015

PNI = 0.011 PSup = 0.32

PNI <0.001PSup <0.001

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

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

5

15

25

Isch

emic

Co

mp

osi

te (

%)

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

Stone GW. ACC 2007 presentation

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-year

UFH/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)

Stone GW. ACC 2007 presentation

Goals of the present analysisGoals of the present analysis

To examine the long-term outcomes of bivalirudin ± GP IIb/IIIa inhibition compared to UFH/Enoxaparin + GP IIb/IIIa inhibition in moderate and high risk ACS patients undergoing PCI

Overall primary clinical endpoints at 1 year

Outcomes in patients switched to bivalirudin monotherapy from UFH or enoxaparin

Analysis of the relative impact of iatrogenic bleeding complications on long-term outcome

To examine the long-term outcomes of bivalirudin ± GP IIb/IIIa inhibition compared to UFH/Enoxaparin + GP IIb/IIIa inhibition in moderate and high risk ACS patients undergoing PCI

Overall primary clinical endpoints at 1 year

Outcomes in patients switched to bivalirudin monotherapy from UFH or enoxaparin

Analysis of the relative impact of iatrogenic bleeding complications on long-term outcome

Management Strategy (N=13,819)Management Strategy (N=13,819)

56.4%

11.1%32.5%CABG (n=1,539)CABG (n=1,539)

Medical Rx (n=4,491)Medical Rx (n=4,491)

PCI (n=7,789)PCI (n=7,789)

UFH/Enox + GP IIb/IIIaN = 2,561

Bivalirudin + GP IIb/IIIaN = 2,609

Bivalirudin aloneN = 2,619

ACUITY PCI: Baseline CharacteristicsACUITY PCI: Baseline Characteristics

UFH/Enox + GP IIb/IIIa

(N=2561)

Bivalirudin + GP IIb/IIIa

(N=2609)

Bivalirudin alone(N=2619)

Age (median [range], yrs) 63 [25-91] 62 [21-95] 63 [30-92]

Male 73% 74% 73%

Weight (median [IQR], kg) 84 [73,96] 84 [74,96] 84 [75,95]

Diabetes 28% 27% 28%

- Insulin requiring 8% 8% 9%

Hypertension 66% 65% 66%

Hyperlipidemia 56% 56% 56%

Current smoker 31% 31% 31%

Prior MI 30% 30% 31%

Prior PCI 38% 38% 40%

Prior CABG 17% 17% 18%

Renal insufficiency* 19% 18% 18%

* creatinine clearance <60 mL/min

Stone GW et al. Lancet 2007;369:907-19

ACUITY PCI: Baseline High Risk FeaturesACUITY PCI: Baseline High Risk Features


(N=2561)

Bivalirudin + GP IIb/IIIa

(N=2609)

Bivalirudin alone

(N=2619)

Cardiac biomarker (CK-MB or trop) 65% 64% 66%

- Troponin 65% 63% 66%

ST-segment ≥1mm 35% 37% 35%

Cardiac biomarker or ST-segments 77% 75% 77%

TIMI Risk Score

0-2* 17% 15% 16%

3-4 52% 55% 53%

5-7 31% 30% 31%

* 84.0% had +biomarkers or baseline ST97% of all pts had +biomarkers or baseline ST, or were TIMI Int/High risk


ACUITY PCI: Primary results – 30 daysACUITY PCI: Primary results – 30 daysUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin AloneUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

8%7%

13%

8%

15%

9% 9%

12%

4%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

UFH/Enox+GPIIb/IIIa (N=2561) Bivalirudin+GPIIb/IIIa (N=2609) Bivalirudin alone (N=2619)

P=0.10 P=0.057

P=0.16 P=0.45

P=0.32 <0.0001


ACUITY PCI: Bleeding – 30 daysACUITY PCI: Bleeding – 30 days


(N=2561)

Bivalirudin + GP

IIb/IIIa(N=2609)

Bivalirudin alone

(N=2619)

PValue*

ACUITY Scale

- Major Bleed, all 7.3% 8.0% 4.2% <0.0001

- Major, non-CABG 7% 8% 4% <0.0001

- Minor, non-CABG 26% 28% 15% <0.0001

TIMI Scale

- Any 8% 9% 5% <0.0001

- Major 2% 2% 0.8% <0.0001

- Minor 8% 8% 4% <0.0001

Transfusions, non-CABG 3% 4% 2% 0.002

*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor*P value for bivalirudin alone vs. heparin + IIb/IIIa inhibitor


ACUITY PCI: Primary Results – 1 YearACUITY PCI: Primary Results – 1 Year

0.1 1 10

Hazard Ratio ±95% CI

Composite Ischemia 1.09 (0.96-1.23)

HR (95% CI)

Mortality 0.95 (0.70-1.30)

Bivalirudin Better UFH/Enox+ IIb/IIIa Better

Mo

rtal

ity

(%)


0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 30 60 90 120 150 180 210 240 270 300 330 360 390

ACUITY PCI: Early and Late MortalityACUITY PCI: Early and Late Mortality

UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin AloneUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

30 day

EstimateP

(log rank)

0.9%0.451.2%0.631.1%

—

EstimateP

(log rank)

3.1%0.702.4%0.482.2%

1 year

—

p=0.78

ACUITY PCI: Influence of 30 day Major Bleeding and MI on Late Mortality

ACUITY PCI: Influence of 30 day Major Bleeding and MI on Late Mortality

0.1 1 10

Hazard Ratio ±95% CI

30 Day Major Bleed 3.16 (2.25-4.42) <0.0001

HR (95% CI)

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

30 Day Myocardial Infarction 2.30 (1.57-3.36) <0.0001

P-Value

ACUITY PCI: Impact of Bleeding on LOSACUITY PCI: Impact of Bleeding on LOS

Patients with Bleeding Event

N=459

Patients without Bleeding Event

N=7318

PValue

Hospital length of stay, median days 5.0 3.0<0.000

1

ACUITY PCI: High Risk* patientsACUITY PCI: High Risk* patients

Risk Ratio±95% CI RR (95% CI)

Hazard Ratio±95% CI HR (95% CI)

UFH/Enox+ IIb/IIIa better

* High risk = ↑Tn, CKMB or ECG Δ’s

0.1 1 10

Bivalirudin better Bivalirudin better

30 day Results 1 year Results

Composite ischemia 1.08 (0.88-1.32)

Major bleeding 0.55 (0.42-0.72)

Mortality 0.94 (0.67-1.31)


ACUITY PCI: Impact of clopidogrelACUITY PCI: Impact of clopidogrel

0.1 1 10

PCI patients 1-year MortalityHazard Ratio ±95% CI HR (95% CI)

Bivalirudin better UFH/Enox + IIb/IIIa better

Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine

Clopidogrel at any time prior to hospitalization, randomization

or end of angiography (n=3,429)

1.02 (0.69-1.50)

Clopidogrel after end of angiography to 30’ post PCI

(n=1,044)

1.14 (0.89-2.03)

Clopidogrel after 30’ post PCI (n=519)

0.43 (0.17-1.11)

No clopidogrel (n=88) 3.20 (0.34-31.1)

ACUITY PCI: Impact of clopidogrelACUITY PCI: Impact of clopidogrel

0.1 1 10

PCI troponin+ patients 1-year MortalityHazard Ratio ±95% CI

HR (95% CI)

Bivalirudin better UFH/Enox + IIb/IIIa Better

Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine

Clopidogrel at any time prior to hospitalization, randomization

or end of angiography (n=1,891)

1.07 (0.66-1.73)

Clopidogrel after end of angiography to 30’ post PCI

(n=649)

1.09 (0.46-2.58)

Clopidogrel after 30’ post PCI (n=307)

0.56 (0.17-1.93)

No clopidogrel (n=51) 3.07 (0.32-29.49)

ACUITY PCI: Switch from Prior AntithrombinACUITY PCI: Switch from Prior Antithrombin

0.1 1 10


0.1 1 10


Switch to Bivalirudin

better

Consistent UFH/Enox + IIb/IIIa better

Switch to Bivalirudin

better


Consistent UFH/Enox + IIb/IIIa better

PCI (n=2528)



PCI HIGH RISK*(n=1988)



PCI (n=2528)

Mortality 0.93 (0.58-1.48)


Mortality 0.99 (0.60-1.63)


0.1 1 10 0.1 1 10Bivalirudin better


ACUITY PCI: Antithrombin Naïve PatientsACUITY PCI: Antithrombin Naïve Patients

PCI (n=1639)






PCI (n=1639)

Mortality 1.08 (0.57-2.04)


Mortality 1.15 (0.54-2.45)

Bivalirudin betterUFH/Enox

+ IIb/IIIa better





Study LimitationsStudy Limitations

This analysis is of post-randomization outcomes

The ACUITY PCI sub-study was under-powered for subgroup comparisons All analyses should be considered hypothesis

generating

This analysis is of post-randomization outcomes

The ACUITY PCI sub-study was under-powered for subgroup comparisons All analyses should be considered hypothesis

generating

Conclusions and Clinical ImplicationsConclusions and Clinical Implications

In patients with moderate and high risk ACS undergoing PCI

Bivalirudin alone results in similar 1 year mortality to UFH/enoxaparin plus GP IIb/IIIa inhibition regardless of patient risk, prior antithrombin therapy and clopidogrel exposure

Switching from UFH or enoxaparin to bivalirudin enables patients to achieve significant reductions in bleeding at 30 days and similar mortality at 1 year

These results substantiate the strong relationship between bleeding complications and late mortality in PCI patients

In patients with moderate and high risk ACS undergoing PCI

Bivalirudin alone results in similar 1 year mortality to UFH/enoxaparin plus GP IIb/IIIa inhibition regardless of patient risk, prior antithrombin therapy and clopidogrel exposure

Switching from UFH or enoxaparin to bivalirudin enables patients to achieve significant reductions in bleeding at 30 days and similar mortality at 1 year

These results substantiate the strong relationship between bleeding complications and late mortality in PCI patients

Documents

Dr. Harvey White on behalf of the ACUITY investigators